Oligosaccharide c-glycoside derivatives

ABSTRACT

The present invention provides a novel process for preparing an oligosaccharide C-glycoside derivative of formula I, comprising reacting a compound of formula II with compound of formula III in the presence of at least one primary or secondary amine and at least one additive [in the formulae, the substituents are as defined herein], and novel oligosaccharide C-glycoside derivatives that can be prepared using the process.

TECHNICAL FIELD

The present invention relates to a process for preparing oligosaccharideC-glycoside derivatives, novel oligosaccharide C-glycoside derivativesthat can be prepared using such process, use thereof as atherapeutically active substance, and pharmaceutical compositionscomprising such oligosaccharide C-glycoside derivatives. The presentinvention also relates to the oligosaccharide C-glycosidation method andthe oligosaccharide C-glycoside derivatives that are used forconjugation or covalent attachment of the oligosaccharides to othersurface of assay plate wells and to other molecules, which are used fordiagnosis methods and/or as therapeutics and molecular probes used indiagnostics and in biomedical research.

BACKGROUND ART

Carbohydrates play important roles in biological systems and thus thesynthesis of carbohydrate derivatives is of interest for the developmentof bioactives, probes, and other functional molecules. C-Glycosidation,the C-C bond formation reaction at the anomeric carbon, of unprotectedcarbohydrates is an important reaction for the synthesis ofcarbohydrate-derived pharmaceuticals, glycoconjugates, and otherfunctional carbohydrate derivatives. However, direct C-glycosidationreactions of unprotected carbohydrates are often difficult, and the C-Cbond formation reaction of unprotected carbohydrates has been consideredas a task of enzymes. One of the difficulties in the reactions ofunprotected carbohydrates may be the presence of polyhydroxy groups inthe carbohydrates. In many reactions of carbohydrates, hydroxy groupsmust be firstly protected to avoid that acidic protons of the hydroxygroups react with reagents and/or that the hydroxy groups interrupthydrogen bonding necessary for the catalysis and stereocontrol. Anotherdifficulty with direct C-glycosidation reactions of unprotectedcarbohydrates lies in the cyclic hemiacetal form of the aldoses.Although the aldehyde carbonyl group of the aldoses may be a good siteto react with nucleophiles, the generation of the aldehyde group fromthe cyclic hemiacetal forms by opening the hemiacetal ring, especiallyfrom 6-membered hemiacetal forms of aldohexose derivatives, is not easyunder mild reaction conditions that do not affect the functional groupsof the carbohydrates and of the reactants used for the C-glycosidationreactions. Therefore, many non-enzymatic chemical C-glycosidationreactions of carbohydrates have been performed on pre-activated forms ofcarbohydrates with protected hydroxy groups or on specific precursorsbearing functional groups for the bond formation at the anomericcarbons. Considering atom- and step-economy, direct reactions onunprotected carbohydrates are more preferable than reactions whichrequire protection and deprotection steps and/or strategies requiringthe synthesis of pre-activated forms for the reactions at the anomericcarbons.

SUMMARY OF INVENTION Technical Problem

C-glycosidation reactions that have been reported of unprotectedcarbohydrates include reactions with relatively highly reactivenucleophiles, such as β-diketones, β-keto esters and related molecules,nitromethane, cyanide, and Wittig and related reagents. C-Glycosidationreactions of unprotected carbohydrates also include reactions withmetal-activated reagents. Whereas these reactions have affordedC-glycosidation products from certain unprotected carbohydrates, thesereactions have limitations. For example, the reactions with β-diketonescan be used only for the synthesis of acetone-attached and relatedC-glycosides because of the use of β-diketones as nucleophiles andbecause of the use of basic conditions under heating. Functional groupsthat are not suited to the synthesis of the β-diketones and/or to thebasic and heating C-glycosidation conditions cannot be introduceddirectly.

Recently C-glycosidation reactions of unprotected carbohydrates withsimple ketones have been reported. However, these reported reactionmethods were mostly developed for monosaccharides.

There are approximately two or three times more hydroxy groups permolecule in di- and trisaccharides, respectively, as in monosaccharides.Because of this and/or because of other reasons, reaction catalysts andconditions that work for C-glycosidation of unprotected monosaccharidesdo not always work efficiently for disaccharides. Thus, to directlysynthesize functionalized C-glycosides from unprotected di- andtrisaccharides, advances were required.

Solution to Problem

The present inventors have found that oligosaccharide C-glycosidederivatives can be prepared under high stereoselective, mild, andatom-economical conditions by the C-glycosidation reaction of di- andtrisaccharide aldopyranoses with ketones using pyrrolidine-boric acidcatalyst systems.

In summary, the followings can be provided by the present invention.

(1) A process for preparing a compound of formula I

comprising

reacting a compound of formula II

with a compound of formula III

wherein

X is C₁₋₇alkyl, C₃₋₇cycloalkyl, halo-C₁₋₇alkyl, C₁₋₇alkoxy,halo-C₁₋₇alkoxy, C₁₋₇alkoxy-C₁₋₇alkyl, (C₁₋₇alkoxycarbonyl)-C₁₋₇alkyl,C₂₋₇alkynyl-C₁₋₇alkyl, or aryl, which are optionally substituted,

R¹ is H, or a sugar residue,

R² is H, or a sugar residue, and

R³ is H, or a sugar residue,

in the presence of at least one primary or secondary amine and at leastone additive.

(2) A process for preparing a compound of I-1

comprising

reacting a compound of formula II

with a compound of formula III

in the presence of at least one primary or secondary amine and at leastone additive to give a compound of formula I

and

reacting the compound of formula I with a reactant,

wherein

X is C₁₋₇alkyl, C₃₋₇cycloalkyl, halo-C₁₋₇alkyl, C₁₋₇alkoxy,halo-C₁₋₇alkoxy, C₁₋₇alkoxy-C₁₋₇alkyl, (C₁₋₇alkoxycarbonyl)-C₁₋₇alkyl,C₂₋₇alkynyl-C₁₋₇alkyl, or aryl, which are optionally substituted,

R¹ is H, or a sugar residue,

R² is H, or a sugar residue,

R³ is H, or a sugar residue,

R⁴ and R⁵ independently from each other are selected from the groupconsisting of H, and C₁₋₇alkyl, phenyl, benzyl, piperidinyl, p-tosyl,and 1-phthalazinyl, which are optionally substituted.

(3) A process for preparing a compound of formula I-1′

comprising

reacting a compound of formula II

with a compound of formula III

in the presence of at least one primary or secondary amine and at leastone additive to give a compound of formula I

and

reacting the compound of formula I with a reactant,

wherein

X is C₁₋₇alkyl, C₃₋₇cycloalkyl, halo-C₁₋₇alkyl, C₁₋₇alkoxy,halo-C₁₋₇alkoxy, C₁₋₇alkoxy-C₁₋₇-alkyl, (C₁₋₇alkoxycarbonyl)-C₁₋₇alkyl,C₂₋₇alkynyl-C₁₋₇alkyl, or aryl, which are optionally substituted,

R¹ is H, or a sugar residue,

R² is H, or a sugar residue,

R³ is H, or a sugar residue, and

R⁴ is H, or C₁₋₇alkyl, phenyl, benzyl, piperidinyl, p-tosyl, or1-phthalazinyl, which are optionally substituted.

(4) A process for preparing a compound of formula I-2

comprising

reacting a compound of formula II

with a compound of formula III

in the presence of at least one primary or secondary amine and at leastone additive to give a compound of formula I

and

reacting the compound of formula I with a reactant,

wherein

X is C₁₋₇alkyl, C₃₋₇cycloalkyl, halo-C₁₋₇alkyl, C₁₋₇alkoxy,halo-C₁₋₇alkoxy, C₁₋₇alkoxy-C₁₋₇alkyl, (C₁₋₇alkoxycarbonyl)-C₁₋₇alkyl,C₂₋₇alkynyl-C₁₋₇alkyl, or aryl, which are optionally substituted,

R¹ is H, or a sugar residue,

R² is H, or a sugar residue,

R³ is H, or a sugar residue, and

Y is optionally substituted aryl.

(5) The process according to any of the above-described (1)-(4), whereinthe at least primary or secondary amine and the at least one additiveare selected from

(a) pyrrolidine and H₃BO₃,

(b) pyrrolidine and B(OMe)₃, and

(c) benzylamine and H₃BO₃.

(6) A compound of any one of formulae I, I-1, I-1′, and I-2, whenevermanufactured according to the process of any of the above-described (1)to (5), or a salt thereof,

wherein

X is C₁₋₇alkyl, C₃₋₇cycloalkyl, halo-C₁₋₇alkyl, C₁₋₇alkoxy,halo-C₁₋₇alkoxy, C₁₋₇alkoxy-C₁₋₇alkyl, (C₁₋₇alkoxycarbonyl)-C₁₋₇alkyl,C₂₋₇alkynyl-C₁₋₇alkyl, or aryl, which are optionally substituted,

R¹ is H, or a sugar residue,

R² is H, or a sugar residue,

R³ is H, or a sugar residue, and

R⁴ and R⁵ independently from each other are selected from the groupconsisting of H, and C₁₋₇alkyl, phenyl, benzyl, piperidinyl, p-tosyl,1-phthalazinyl, and which are optionally substituted, and

Y is optionally substituted aryl.

(7) The compound according to the above-described (4) or a salt thereof,wherein the compound is of formula I-1, I-1′, or I-2.

(8) The compound according to the above-described (4) or a salt thereof,wherein the compound is selected from

(9) A pharmaceutical composition, comprising the compound according toany of the above-described (6) to (8) or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier.

DESCRIPTION OF EMBODIMENTS

One embodiment of the present invention provides a process for preparinga compound of formula I, i.e. an oligosaccharide C-glycoside derivative,

comprising

reacting a compound of formula II

with a compound of formula III

wherein

X is C₁₋₇alkyl, C₃₋₇cycloalkyl, halo-C₁₋₇alkyl, C₁₋₇alkoxy,halo-C₁₋₇alkoxy, C₁₋₇alkoxy-C₁₋₇alkyl, (C₁₋₇alkoxycarbonyl)-C₁₋₇alkyl,C₂₋₇alkynyl-C₁₋₇alkyl, or aryl, which are optionally substituted,

R¹ is H, or a sugar residue,

R² is H, or a sugar residue, and

R³ is H, or a sugar residue,

in the presence of at least one primary or secondary amine and at leastone additive.

The amount of each compound used in the process of the present inventioncan be at any amount as long as the reaction can proceed and the presentinvention can be carried out. The molar ratio of the compound of formulaIII to the compound of formula II is, for example, 2 to 100, preferably4 to 40, and more preferably 4 to 30. The molar ratio of the total molaramount of the at least primary or secondary amine to the molar amount ofthe compound of formula II is, for example, 0.05 to 1.0, preferably 0.1to 0.8, and more preferably 0.4 to 0.6. The molar ratio of the totalmolar amount of the at least one additive to the molar amount of thecompound of formula II is, for example, 0.05 to 5.0, preferably 0.2 to3.0, and more preferably 1.0 to 2.0.

The above reaction can be carried out in any solvent as long as thereaction can proceed and the present invention can be carried out.Examples of the solvents include, but are not limited to, polar solventssuch as MeOH, DMSO, and the like. The reaction time is not particularlylimited but, for example, for 12 to 120 hours, preferably for 12 to 96hours, and more preferably for 24 to 96 hours. The above reactiontemperature can be, for example, at 10-60° C., preferably at 15-40° C.,and more preferably at 20-30° C.

The term “C₁₋₇alkyl” as used herein denotes a monovalent linear orbranched saturated hydrocarbon group having 1 to 7 carbon atoms,preferably 1 to 4 carbon atoms. Examples of C₁₋₇alkyl include, but arenot limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, and heptyl. Preferable are methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, and isopentyl, and more preferable are methyl, ethyl, propyl,isopropyl, isobutyl, tert-butyl, and isopentyl.

The term “C₃₋₇cycloalkyl” as used herein denotes a monovalent saturatedcarbocyclic group having 3 to 7 carbon atoms, preferably 3 to 6 carbonatoms, as ring atoms. Examples of C₃₋₇cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “halo-C₁₋₇alkyl” as used herein denotes the C₁₋₇alkyl of whichat least one carbon atom is substituted with halogen(s). When two ormore halogens are substituted to the same carbon atom or differentcarbon atoms, the halogens may be same or different. Preferable issubstitution with 1 to 5 halogen atoms, and more preferable issubstitution with 1 to 3 halogen atoms. Examples of halogen include, butare not limited to, fluorine, chlorine, bromine, and iodine. Preferableare fluorine, chlorine, and bromine, and more preferable are fluorineand chlorine. Examples of halo-C₁₋₇alkyl include, but are not limitedto, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl,1,1,1-trifluoropropyl, and pentafluoroethyl.

The term “C₁₋₇alkoxy” as used herein denotes a group in which an oxygenatom is linked to the C₁₋₇alkyl. C₁₋₇alkoxy can be shown by the formulaof C₁₋₇alkyl-O—. Examples of C₁₋₇alkoxy include, but are not limited to,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,and tert-butoxy.

The term “halo-C₁₋₇alkoxy” as used herein denotes the C₁₋₇alkoxy ofwhich at least one carbon atom is substituted with halogen(s). When twoor more halogens are substituted to the same carbon atom or differentcarbon atoms, the halogens may be same or different. Preferable issubstitution with 1 to 5 halogen atoms, and more preferable issubstitution with 1 to 3 halogen atoms. Examples of halogen include, butare not limited to, fluorine, chlorine, bromine, and iodine. Preferableare fluorine, chlorine, and bromine, and more preferable are fluorineand chlorine. Examples of halo-C₁₋₇ alkoxy include, but are not limitedto, fluoromethoxy, difluoromethoxy, trifluoromethoxy,1,1,1-trifluoroethoxy, 1,1,1-trifluoropropoxy, and pentafluoroethoxy.

The term “C₁₋₇alkoxy-C₁₋₇alkyl” as used herein denotes the C₁₋₇alkyl ofwhich at least one carbon atom is substituted with the C₁₋₇alkoxy.Examples of the C₁₋₇alkoxy-C₁₋₇ alkyl include, but are not limited to,methoxymethyl, dimethoxymethyl, tetrahydrofuran-3-yl-methyl, andtetrahydropyran-4-yl-methy.

The term “C₁₋₇alkoxycarbonyl” as used herein denotes a group in whichC₁₋₇alkoxy is bonded with —CO— group. The C₁₋₇alkoxycarbonyl can beshown by the formula of C₁₋₇ alkoxy-CO—.

The term “(C₁₋₇alkoxycarbonyl)-C₁₋₇alkyl” as used herein denotes theC₁₋₇alkyl of which at least one carbon atom is substituted with at leastone C₁₋₇alkoxycarbonyl. Examples of optionally substituted(C₁₋₇alkoxycarbonyl)-C₁₋₇alkyl include, but are not limited tomethoxycarbonyl-methyl, ethoxycarbonyl-metyl, methoxycarbonyl-ethyl,ethoxycarbonyl-ethyl, methoxycarobnyl-propyl, ethoxycarbonyl-propyl,methoxy-carbonyl-butyl, ethoxycarbonyl-butyl, andbenzyloxycarbonyl-propyl, and preferable are 2-(ethoxycarbonyl)-1-ethyl,3-(methoxycarbonyl)-1-propyl, 3-(ethoxycarbonyl)-1-propyl,4-(ethoxycarbonyl)-1-butyl, and 3-(benzyloxycarbonyl)-1-propyl,

The term “C₂₋₇alkynyl” as used herein denotes a monovalent linear orbranched hydrocarbon group containing a C-C triple bond and having 2 to7 carbon atoms, preferably 4 to 6 carbon atoms. Examples of C₂₋₇alkynylinclude, but are not limited to, ethynyl, propynyl, butynyl, pentynyl,hexynyl, and heptynyl. Preferable are butynyl, and hexynyl, and morepreferable are but-3-ynyl and hex-5-ynyl.

The term “C₂₋₇alkynyl-C₁₋₇alkyl” as used herein denotes the C₁₋₇alkyl ofwhich at least one carbon atom is substituted with at least one C₂₋₇alkynyl. Example of the C₂₋₇ alkynyl-C1-7alkyl include, but are notlimited to di(but-3-ynyl)methyl, 2,2-di(hex-5-ynyl)ethyl,3,5-di(hex-5-ynyl)cyclohexyl, and 2-(but-3-ynyl)propyl.

The term “aryl” as used herein denotes a monovalent aromatic carbocyclicor heterocyclic group. Examples of optionally substituted aryl include,but are not limited to phenyl, phenyl substituted with C₁₋₇, nitro,halogen, and the like, thiophenyl, furanyl, benzofuranyl, naphthyl, andquinolinyl, and preferable are phenyl, 4-methylphenyl, 4-nitrophenyl,4-bromophenyl, thiophen-2-yl, furan-2-yl, benzofuran-2-yl, naphth-1-yl,naphth-2-yl, and quinolin-3-yl.

The term “sugar residue” as used herein refers to a substituent which isderived from a sugar and in which one of OH group does not exist inorder to form a bonding site. The sugar can be monosaccharide,disaccharide, oligosaccharide, or polysaccharide, which are optionallysubstituted. The saccharide can include aminosaccharide. Examples of thesugar residue include, but are not limited to a glucose residue, asialic acid reside, and other carbohydrate resides.

The term “glucose residue” as used herein refers to a substituent whichis derived from glucose and in which one of OH group in glucose does notexist and such site becomes a bonding site. For example, the glucoseresidue can be a glucosyl group. Examples of the glucosyl group include,but are not limited to, β-D-glucosyl, α-D-glucosyl, β-L-glucosyl, andα-L-glucosyl.

The term “sialic acid residue” as used herein refers to a substituentwhich is derived from sialic acid and in which one of OH group in sialicacid does not exist and such site becomes a bonding site. For example,the sialic acid residue can be a sialyl group. Examples of the glucosylgroup include, but are not limited to, β-sialyl and α-sialyl.

Examples of other carbohydrate residue include, but are not limited toβ-D-mannosyl, α-D-mannosyl, β-D-galactosyl, α-D-galactosl,N-acetyl-β-D-mannosaminyl, N-acetyl-α-D-mannosaminyl,N-acetyl-β-D-glucosaminyl, N-acetyl-α-D-glucoosaminyl,N-acetyl-β-D-galactosaminyl, N-acetyl-α-D-galactosaminyl,glucosyl-glucosyl, glucosyl-mannosyl, glucosyl-galactosyl,mannosyl-glucosyl, galactosyl-glucosyl,N-acetyl-α-D-mannosaminyl-glucosyl, and sialyl-lactosyl.

As the “primary or secondary amine” in the above-described process, anyprimary or secondary amine can be used as long as the reaction canproceed and the present invention can be carried out. Such primary orsecondary amines include, but are not limited to, aliphatic amines(e.g., benzylamine, methylamine, dimethylamine, ethylamine,diethylamine, and the like), heterocyclic amines (e.g., pyrrolidine,piperidine, piperazine, morpholine, and the like), and a combinationthereof. Preferable are 5- or 6-membered heterocyclic primary orsecondary amines, and primary amines such as benzylamine, and morepreferable is pyrrolidine.

As the “additive” in the present invention, any additive can be used aslong as the process can proceed and the present invention can be carriedout. Such additives include, but are not limited to, boric acid (e.g.,H₃BO₃), boric compounds, and a combination thereof. The boric compoundsinclude, but are not limited to, trimethyl borate (e.g., B(OMe)₃).Preferable are boric acid and trimethyl borate, and more preferable isboric acid.

Another embodiment of the present invention provides a process forpreparing a compound of I-1

comprising

reacting a compound of formula II

with a compound of formula III

in the presence of at least one primary or secondary amine and at leastone additive to give a compound of formula I

and

reacting the compound of formula I with a reactant,

wherein

X, R¹, R², and R³ are as defined above, and

R⁴ and R⁵ independently from each other are selected from the groupconsisting of H, and C₁₋₇alkyl, phenyl, benzyl, piperidinyl, p-tosyl,and 1-phthalazinyl, which are optionally substituted.

Still another embodiment of the present invention provides a process forpreparing a compound of formula I-1′

comprising

reacting a compound of formula II

with a compound of formula III

in the presence of at least one primary or secondary amine and at leastone additive to give a compound of formula I

and

reacting the compound of formula I with a reactant,

wherein

X, R¹, R², and R³ are as defined above, and

R⁴ is H, or C₁₋₇alkyl, phenyl, benzyl, piperidinyl, p-tosyl, or1-phthalazinyl, which are optionally substituted.

The “reactant” used in the above reaction can be a hydrazine derivative.The hydrazine derivatives include, but are not limited to,methylhydrazine, dimethyl-hydrazine, phenylhydrazine, benzylhydrazine,piperidinehydrazine, p-tosylhydrazine, 1-phthalazinylhydrazine, and thelike, and preferable is p-tosyl hydrazine. The amount of the reactant tobe used is not particularly limited as long as the reaction can proceedand the present invention can be carried out.

The above reaction can be carried out in any solvent as long as thereaction can proceed and the present invention can be carried out. Suchsolvents include, but are not limited to DMF, DMSO, EtOH, MeOH, THF, andthe like. The reaction time is not particularly limited as long as thereaction can proceed and the present invention can be carried out butis, for example, for 10 to 24 hours. The above reaction can be carriedout, for example, at 0 to 40° C.

Still yet another embodiment of the present invention provides a processfor preparing a compound of formula I-2

comprising

reacting a compound of formula II

with a compound of formula III

in the presence of at least one primary or secondary amine and at leastone additive to give a compound of formula I

and

reacting the compound of formula I with a reactant,

wherein

X, R¹, R², and R³ are defined above, and

Y is optionally substituted aryl, in particular 6-methoxynaphth-2-yl.

The “reactant” used in the above reaction can be6-methoxy-2-naphthaldehyde, or arylaldehydes. The amount of the reactantto be used is not particularly limited as long as the reaction canproceed and the present invention can be carried out.

The above reaction can be carried out using catalysts (such asL-proline-i-Pr₂NEt, and pyrrolidine-boric acid) in any solvent (such asDMSO) as long as the reaction can proceed and the present invention canbe carried out.

When any one of X, R¹ to R⁵ and Y has an optional substituent, suchsubstituent can be independently from each other and selected from, forexample, halogen, C1-7alkyl, C1-7alkoxy, aryl, nitro, cyano, amino,benzyloxycarbonylamino, tert-butoxycarbonylamino, ester, amide, and thelike.

In preferable embodiments of the present invention, the at least oneprimary or secondary amine and the at least one additive are selectedfrom

(a) pyrrolidine and H₃BO₃,

(b) pyrrolidine and B(OMe)₃, and

(c) benzylamine and H₃BO₃.

In one aspect, the present invention provides novel compounds shown byany one of formulae I, I-1, I-1′, and I-2, and such compounds can bemanufactured according to the process as described hereinbefore, or asalt thereof,

In these formulae, each symbol has the same meaning as definedhereinabove.

The compounds of formula I I-1, I-1′, and I-2 may contain severalasymmetric centers and be present in the form of enantiomerically puresingle enantiomers, mixtures of enantiomers (e.g., racemates) of singlediastereomers, enantiomerically pure forms of diastereoisomer mixtures,mixtures of diastereoisomers, single di-astereoisomer racemates, ormixtures of diastereoisomeric mixtures' racemates. The optically pureform can be obtained by, for example, reactions of enantiomerically pureforms of II, optical resolution of the racemates, asymmetric synthesis,or asymmetric chromatography (e.g., chromatography using a chiralcarrier or eluent).

In one embodiment of the above aspect, the compound is the compound offormula I-1, I-1′, I-2, or a salt thereof.

In another embodiment of the above aspect, the compound is selected fromthe followings, or a salt thereof:

The present invention also provides a pharmaceutical composition,comprising the compound of formula I, I-1, I-1′, or I-2, or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

The “salt” of the compound may be any salt as long as the presentinvention can be carried out. The salt may be an acid-addition salt withan inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like, in particularhydrochloric acid, and with an organic acid such as acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcysteine, and the like. In addition, the salt may be a saltwhich can be prepared by the reaction of the compound in a free acidform with an inorganic base or an organic base. Such salts prepared withinorganic bases include, but are not limited to, sodium salts, potassiumsalts, lithium salts, ammonium salts, calcium salts, magnesium salts,and the like. Salts prepared with organic bases include, but are notlimited to, salts with primary, secondary, or tertiary amines,substituted amines, including naturally occurring substituted amines,cyclic amines, and basic ion exchange resins. Such salts may be saltswith isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine,piperidine, polyimine resins, and the like. When the salt is contained apharmaceutical composition, a pharmaceutically acceptable salt ispreferable.

The pharmaceutical composition can be formulated into a pharmaceuticalpreparation. The pharmaceutical preparation may be for oraladministration, for example, in the form of tablets, coated tablets,dragees, hard or soft capsules, solutions, emulsions, or suspensions, ormay be for rectal administration, for example, in the form ofsuppositories, or may be for parenteral administration, for example, inthe form of injection solutions.

The pharmaceutical composition can contain a pharmaceutically acceptablecarrier such as pharmaceutically acceptable inorganic or organicexcipients suitable for the production of tablets, coated tablets,dragees, and soft or hard gelatin capsules.

Examples of the excipient suitable for the production of tablets,dragees, and hard gelatin capsules include, but are not limited to,lactose, corn starch or derivatives thereof, talc, stearic acid or itssalts, and the like.

Examples of the excipient suitable for the production of soft gelatincapsules include, but are not limited to, vegetable oils, waxes, fats,semisolid polyols, liquid polyols, and the like.

Examples of the excipient suitable for the production of solutions andsyrups include, but are not limited to, water, polyols, saccharose,invert sugar, glucose, and the like.

Examples of the excipient suitable for the production injectionsolutions include, but are not limited to, water, alcohols, polyols,glycerol, vegetable oils, and the like.

Examples of the excipient suitable for the production of suppositoriesinclude, but are not limited to, natural or hardened oils, waxes, fats,semiliquid polyols, liquid polyols, and the like.

Other than the excipient, the pharmaceutical composition can containadditive(s) that are generally used for manufacturing a medicament,where necessary. Examples of such additive include, but are not limitedto, preservatives, solubilizers, stabilizers, wetting agents,emulsifiers, sweeteners, colorants, flavorants, salts for modifying theosmotic pressure, buffers, masking agents, and antioxidants.

If desired, the pharmaceutical composition may contain two or morepharmaceutically active ingredients.

The dosage may be varied according to sex, age, condition, and the likeof the subject to be administered. In general, in the case of oraladministration, a daily dosage of about 10 mg to about 1000 mg of thecompound of formula I, I-1, I-1′, or I-2 could be appropriate. Thedosage can be administered in a single dose or a divided dose.

The present invention provides a novel process for preparingoligosaccharide C-glycoside derivatives that can be conducted under highstereoselective, mild, and atom-economical conditions, and by suchprocess, novel oligosaccharide C-glycoside derivatives that could not beobtained by the previously known methods can be prepared. The presentinventive process is step- and atom-economical (i.e., shorter reactionroutes, less waste generation compared to the previously known methods).The present inventive compounds can be used as therapeutics, bioactives,bioactive candidates, probes, and the like, as well as their synthonsand components. For example, glucose-bearing-carbohydrate-fluorescentmolecule conjugates can be used for visualization ofglucose-transporter-enriched cells. Glucose-bearing-carbohydrate-cancerdrug conjugates can be used to deliver the conjugated drugs to cancercells more efficiently. Sialyllactose-fluorescent molecule conjugatescan be used for visualization of viruses. Depending on the carbohydratestructure, the molecules can provide antibacterial and/or antiviralactivities. The present inventive process can be used for theconjugation or covalent attachment of oligosaccharides to surface ofassay plate wells and to other molecules, which are used for diagnosismethods and/or as therapeutics and molecular probes used in diagnosticsand in biomedical research.

Hereafter, the present invention will be explained in more detail.

C-Glycosides bearing ketone groups have been used for the synthesis ofvarious C-glycoside derivatives. The inventors designed hereinC-glycosidation of unactivated and unprotected di- and trisaccharidealdoses with ketones. In the inventors' design, the following pointswere considered to develop the C-glycosidation reactions: (1) insitu-activation of aldopyranoses to enable the C-C bond formation at theanomeric center, (2) in situ-generation of enamines or enolates fromketones that react as nucleophiles with aldopyranoses, (3) catalystsystems that work in the presence of polyhydroxy-substituted compounds,and (4) reaction systems/catalyst systems that provide highstereoselectivity for the C-C bond formation without altering thecarbohydrate stereochemistry. The inventors sought amine-based catalyststo address these points and to enable the generation of desired productsunder mild conditions. In the inventors' design, amine catalysts wereexpected to form enamines of ketones. At the same time, the catalystsystems would activate the carbohydrates to lead the C-C bond formation.Based on these considerations, the inventors searched for catalysts ofthe C-glycosidation.

The inventors previously reported C-glycosidation of unprotected2-N-acyl-aldopyranoses (Johnson, S.; Tanaka, F. Org. Biomol. Chem. 2016,14, 259-264). In this reaction, some catalyst systems were efficientonly for specific carbohydrates and the efficiency of the catalystsystems depended on the carbohydrate structure/stereochemistry.

For the C-glycosidation of di- and trisaccharide aldopyranoses withketones, the inventors focused on the development of the catalystsystems that work for a series of carbohydrates, includingfunctionalized carbohydrates, and for various ketones.

As described below, the catalyst systems composed of pyrrolidine andboric acid accelerated the C-glycosidation reactions of unprotected di-and trisaccharides with ketones.

C-Glycosidation of Monosaccharide Aldopyranoses

The inventors reasoned that catalyst systems that work for theC-glycosidation of di- and trisaccharide aldopyranoses with ketonesshould work for C-glycosidation of monosaccharide aldopyranoses to somedegree. By analyzing the C-glycosidation products from monosaccharidealdopyranoses, features of the reactions, such as the possibility ofisomerization at the 2-position of the carbohydrates, would be moreeasily recognized than by analyzing the products from di- andtrisaccharides. Thus, first, the results of the C-glycosidationreactions of monosaccharide aldopyranoses are described. When thereaction was performed using pyrrolidine and boric acid as catalyst,C-glycoside ketone 3aa was obtained (Table 1).

For the reaction of D-glucose (1a) with acetone (2a), amine-basedcatalyst systems that have been commonly used in aldol and/or Mannichreactions of ketones with simple aldehydes (i.e., not carbohydrates),such as proline and amino acids, did not give 3aa. As 6-memberedhemiacetals are usually stable as the cyclic forms, aldopyranoses, suchas D-glucose, are more difficult to react with nucleophiles at theanomeric carbon (or the aldehyde carbonyl group of the correspondingring-opened form) than are aldopentoses such as ribose. Conditions usedfor catalyzing the C-glycosidation of ribose with simple ketones, suchas proline-DBU, were also not optimal for the C-glycosidation ofD-glucose with acetone.

In the presence of pyrrolidine and boric acid, the reaction of D-glucose(1a) with ethyl 5-oxohexanoate (2b) also afforded C-glycoside product3ab (Table 1). The ester group of ketone 2b was not affected under thepyrrolidine-boric acid catalysis conditions. Reaction with acetophenone(2c) also afforded the corresponding C-glycoside 3ac. The reactions ofC₆-aldoses bearing 2-hydroxy group with acetophenone were previouslyrecognized as difficult reactions (Wei, X.; Shi, S.; Xie, X.; Shimizu,Y.; Kanai, M. ACS Catal. 2016, 6, 6718-6722). The reaction of D-mannose(1b) with ketone 2b also afforded C-glycosidation product 3bb when thepyrrolidine-boric acid combination was used as a catalyst.

TABLE 1 C-Glycosidation of monosaccharide aldohexopyranoses.^(a)

1 product 3 yield

25%^(b) 12%^(c)

37%

17%

20% ^(a)Conditions: Carbohydrate 1 (0.50 mmol), ketone 2 (2.0 mmol),pyrrolidine (0.25 mmol), H₃BO₃ (1.0 mmol) in DMSO (1.0 mL) at roomtemperature (25° C.) for 48 h. ^(b)Acetone (5.0 mmol). ^(c)Acetone (20equiv to 1a), boric acid (1.0 equiv to 1a), 24 h; modified conditions;see the Examples.

Under the pyrrolidine-boric acid catalysis conditions, isomerization atthe 2-position of the carbohydrates did not occur: The reaction ofD-glucose affording 3ab did not co-generate 3bb, and the reaction ofD-mannose affording 3bb did not form 3ab.

Isolated products 3 were stable at room temperature (25° C.) for atleast one month. Acetal formation at the ketone group of these productsand the formation of ring-opened forms were negligible or were notdetected.

Previously reported C-glycosidation reactions of C₆-aldoses with ketones(excluding 1,3-diketones and relatively nucleophilic ketones) were oftenperformed with aldoses that did not have a hydroxy group at the2-position of the aldoses. The pyrrolidine-boric acid catalyst systemallowed the synthesis of C-glycoside derivatives of C₆-aldopyranosesbearing a hydroxy group at the 2-position. Further, in the reactionscatalyzed by the pyrrolidine-boric acid system, products were obtainedas single diastereomers or with high diastereoselectivity with theβ-isomer as the major diastereomer (dr (β-anomer/α-anomer)>10:1 to>20:1).

Until the present invention, C-glycoside products bearing ketonemoieties were synthesized by the reactions of unprotected carbohydrateswith β-diketones (Richter, C.; Krumrey, M.; Bahri, M.; Trunschke, S.;Mahrwald, R. ACS Catal. 2016, 6, 5549-5552) or withHorner-Wadsworth-Emmons (HWE) β-carbonyl phosphonate reagents (Ranoux,A.; Lemiegre, L.; benoit, M.; Guegan, J.-P.; Benvegnu, T. Eur. J. Org.Chem. 2010, 1314-1323). These reactions were performed at hightemperature under basic conditions. The reactions of unprotectedcarbohydrates with ketones using pyrrolidine-boric acid catalystafforded the products under mild conditions at room temperature. Withthe use of pyrrolidine-boric acid catalysis system, methyl ketonederivatives with the ester group and with the aryl group were able to beused as nucleophiles, and the synthesis of β-diketones and of HWEreagents was not required to obtain the C-glycoside products.

C-Glycosidation of Disaccharide Aldopyranoses

^(a) Conditions: Carbohydrate 4 (0.5 mmol, 1.0 equiv), ketone 2 (2.0mmol, 4.0 equiv), pyrrolidine (0.25 mmol, 0.5 equiv), H₃BO₃ (1.0 mmol,2.0 equiv) in DMSO (1.0 mL) at room temperature (25° C.) for 48 h. ^(b)Modified conditions with 4 (1.0 equiv), acetone (20 equiv), pyrrolidine(0.5 equiv), and H₃BO₃ (1.0 equiv); see the Examples. ^(c) 96 h.

C-Glycosidation reactions of disaccharide aldopyranoses 4 are shown inScheme 1. Under the pyrrolidine-boric acid catalysis conditions,reactions of D-lactose (4a) with ketones afforded the correspondingC-glycosidation products 5aa-5ah (Scheme 1). These products wereβ-isomers (dr ((β/α)>10:1) regardless of the reaction time lengths.Reactions with various ketones, such as acetone, unsymmetricalfunctionalized alkyl methyl ketones (including ketones bearing an estergroup, an ethynyl group, or a cyclopropane ring), and aryl methylketones, afforded the desired C-glycosidation products.

When amine-based catalyst systems were screened to afford 5aa in thereaction of D-lactose (1a) with acetone, commonly used amine-basedcatalysts such as proline did not catalyze the reaction. Proline withbases such as N,N-diisopropylethylamine also did not efficientlycatalyze the reaction. Among catalyst systems tested, pyrrolidine-boricacid most efficiently catalyzed the reaction. Investigation of catalystsystems for the reaction of 4a is further discussed in the later part(see below).

Under the pyrrolidine-boric acid catalysis conditions, reactions ofD-maltose (4b) and of D-cellobiose (4c) also afforded the correspondingC-glycosides 5ba and 5ca, respectively (Scheme 1). Products 5ba and 5cawere also obtained as β-isomers (dr (β/α)>10:1).

The pyrrolidine-boric acid catalysis conditions did not affect thestereochemistry of the O-glycosylated carbon of the disaccharide (i.e.,the 1′-position of the disaccharides) (Scheme 1). In the reaction ofD-maltose (4b) affording 5ba, the formation of 5ca was not observed, andin the reaction of D-cellobiose (4c) affording 5ca, the formation of 5bawas not detected. For products 5 obtained from D-lactose, in the ¹H NMRspectra, the coupling constant J value of the proton at the 1′-positionindicated that the stereochemistry of the 1′-position of the reactantwas retained in the products.

Reactions of disaccharides 4a, 4b, and 4c were faster than reactions ofmonosaccharides 1 under the same pyrrolidine-boric acid catalysisconditions when the reactions with the same ketones were compared. Theyields of the disaccharide C-glycoside derivatives after 48 h werebetter than those of monosaccharide C-glycoside derivatives when thesame ketones were used under the same reaction conditions (Scheme 1, 5abversus Table 1, 3ab and 3bb; Scheme 1, 5ac versus Table 1, 3ac). Yieldsof products 5 were improved with longer reaction time without increasedformation of by-products (Scheme 1, for 5aa: 45% after 48 h, 61% after96 h; for 5ab: 45% after 48 h, 65% after 96 h; for 5ag: 35% after 48 h,55% after 96 h).

In contrast, for D-melibiose (4d) in which the hydroxy group at the6-position of the terminal aldopyranose is glycosylated, thecorresponding C-glycosidation products were not formed under thepyrrolidine-boric acid catalysis conditions.

C-Glycosidation of Trisaccharide Aldopyranoses

Reactions of trisaccharide aldopyranoses 6 were also performed usingpyrrolidine-boric acid catalysis conditions. With the use of thepyrrolidine-boric acid catalyst system, reactions of 3′-sialyllactose(6a), 6′-sialyllactose (6b), and maltotriose (6c) with ketones affordedthe corresponding C-glycosides 7 (Scheme 2). Reactions with acetone,alkyl methyl ketones bearing various functional group or a cyclopropanering, and aryl methyl ketones all gave the desired C-glycoside ketones7. Use of the pyrrolidine-boric acid catalyst system allowed the directC-glycosidation reactions of highly functionalized carbohydrates such asN-acetylneuraminic acid-bearing carbohydrates.

Transformations of C-Glycoside Ketones

Scheme 5 Derivatization through oxime formation followed by amideformation.

The methyl ketone moiety of monosaccharide C-glycoside ketones and of afew disaccharide C-glycosides has been used as a reaction site forchemical transformations to derivatize the C-glycoside ketones. TheC-glycoside ketones synthesized using the pyrrolidine-boric acidcatalysis conditions were transformed to C-glycoside derivatives withmore complex and/or elongated structures (Schemes 3, 4, and 5). Themethyl ketone moiety was used as a nucleophile (via the formation ofenamines or enolates) to generate aldol condensation products 8 (Scheme3). The methyl ketone moiety was also used as an electrophile to formhydrazone derivative 9 and oxime derivative 10 (Schemes 4 and 5).

Carbohydrate derivatives bearing a 6-methoxynaphthalen-2-yl-buten-2-onemoiety are inhibitors of certain cancer-associated enzymes. Until thepresent invention, monosaccharide C-glycoside ketones have beenderivatized to afford aldol condensation products. In the presentinvention, di- and trisaccharide C-glycosides were transformed to thecorresponding aldol condensation products 8a-e using eitherproline-N,N-diisopropylethylamine or pyrrolidine-boric acid catalysissystems (Scheme 3). No protection of the polyhydroxy groups of theC-glycosides was necessary before the transformation. Through theformation of 8, the formation of 5 and 7 in the C-glycosidationreactions was further confirmed.

The C-glycosidation using the pyrrolidine-boric acid catalysis allowedthe synthesis of C-glycoside ketones bearing functional groups (such asethynyl, ester, and aryl ketone groups) as described above. Thesefunctional groups will also be useful for further derivatization.

Catalyst Systems in the C-Glycosidation

To understand the key factors that result in the generation of theC-glycosides from di- and trisaccharide aldopyranoses usingpyrrolidine-boric acid catalysis system, related catalyst systems werealso evaluated in the reaction of D-lactose (4a) with ketone 2b toafford 5ab and with ketone 2c to afford 5ac (Table 2).

TABLE 2 Catalyst systems for the C-glycosidation of 4a.^(a)

entry catalyst system product yield (%) 1 pyrrolidine-H₃BO₃ 5ab 45^(b) 2pyrrolidine-B(OMe)₃ 5ab 39  3 pyrrolidine-NaOH 5ab —^(c) 4pyrrolidine-Na₂CO₃ 5ab —^(c) 5 pyrrolidine-DBU 5ab <5  6pyrrolidine-NH₄Cl 5ab —^(c) 7 pyrrolidine-phenol 5ab <5  8pyrroldiine-CH₃COOH 5ab <5  9 Et₃N-H₃BO₃ 5ab —^(c) 10 DBU-H₃BO₃ 5ab—^(c) 11 pyrrolidine 5ab —^(c) 12 H₃BO₃ 5ab —^(c) 13 pyrrolidine-H₃BO₃5ac 36^(b) 14 PhCH₂NH₂-H₃BO₃ 5ac 30  ^(a)Conditions: For entry 2,carbohydrate 4a (0.25 mmol), ketone 2b or 2c (2.0 mmol), pyrrolidine(0.13 mmol), B(OMe)₃ (0.5 mmol) in DMSO (0.5 mL) at room temperature(25° C.) for 48 h. For entries 3-12 and 14, H₃BO₃ and/or pyrrolidinewere subtracted or replaced as indicated. ^(b)Data from Scheme 1.^(c)Formation of 5ab was not detected.

Pyrrolidine alone or boric acid alone did not catalyze the reaction toform the C-glycosidation product; carbohydrate 4a remained unreacted(entries 11 and 12). Substituting boric acid with bases, such as NaOH,Na₂CO₃, or DSU, in the catalyst system also did not afford 5ab (entries3-5). Substituting boric acid with NH₄Cl, phenol, or acetic acid alsodid not form the product (entries 6-8). On the other hand, thepyrrolidine-trimethyl borate catalyst system catalyzed the reaction toafford product 5ab (entry 2). These results suggest that boric acid inthe pyrrolidine-boric acid catalysis in the C-glycosidation acts notjust as a Broensted acid or base. It is likely that boric acid forms B—Ocovalent bonds with the carbohydrate. This B—O covalent formation may bekey to the formation of the C-glycosidation product (see below).

Further, the use of Et₃N or DBU instead of pyrrolidine in thepyrrolidine-boric acid catalysis system did not catalyze the reaction togive the C-glycosidation product (entries 9 and 10). Although DBU hasbeen used to generate enolates from ketones, the DBU-boric acid systemwas not effective for the C-glycosidation with ketones. However,substituting pyrrolidine with benzylamine in the pyrrolidine-boric acidcatalysis system did afford C-glycosidation product 5ac (entry 14).Benzylamine has been used as an amine component in enamine-formingcatalyst systems (Cui, H.-L.; Chouthaiwale, P. V.; Yin, F.; Tanaka, F.Asian J. Org. Chem. 2016, 5, 153-161). These results indicated that bothpyrrolidine (or amine, which can form an imine/iminium ion/enamine) andboric acid (or borate) have functions for catalyzing the C-glycosidationreaction. These results suggest that the pyrrolidine-boric acid catalystsystem involves both the formation of an iminium ion with thecarbohydrate and the formation of an enamine of the ketones during thecatalysis.

The present invented C-glycosidation reaction methods that use thepyrrolidine-boric acid catalyst system allow access to di- andtrisaccharide-derived C-glycosides derivatives including those that werepreviously difficult to synthesize. Insights obtained from ourinvestigation on the mechanisms of the pyrrolidine-boric acid catalysisfor the C-glycosidation will be useful for the development of relatedcatalyzed reactions.

It is to be understood that as used herein and in the claims, thesingular forms “a,” “an,” and “the” should generally be construed tomean “one or more” and include plural reference unless the contextclearly dictates otherwise.

It is also to be understood that the scope of the invention should notbe limited to the particular forms disclosed herein and the inventioncovers all modifications, equivalents, and alternatives falling withinthe spirit and scope of the invention as defined by the claims.

EXAMPLES

The following examples further illustrate the present invention but, ofcourse, should not be construed as limiting the scope of the inventionin any way.

1. C-Glycosidation of Monosaccharide Aldopyranoses (Table 1) GeneralProcedure for the Synthesis of C-glycosides 3

A mixture of carbohydrate (0.50 mmol, 1.0 equiv) and ketone (2.0 mmol,4.0 equiv) in DMSO (1.0 mL) was stirred at room temperature (25° C.) for5 min to solubilize the carbohydrate. To the solution, pyrrolidine (0.25mmol, 0.5 equiv) and boric acid (1.0 mmol, 2.0 equiv) were added and themixture was stirred at the same temperature for 48 h. The mixture waspurified by silica gel flash column chromatography (CH₂Cl₂/MeOH orCHCl₃/MeOH) to give the corresponding C-glycoside 3.

In our observation, after 48 h reaction time, starting materialcarbohydrate 1 remained significantly, and thus the moderate yields of 3were obtained. The corresponding hemiketal forms were possibly generatedas a portion during the reactions depending on reaction conditions andalso depending on carbohydrates and ketones used in the reactions,although they were not isolated or confirmed.

Compound 3aa was synthesized by the general procedure from D-glucose (90mg, 0.50 mmol) but using 10 equiv of acetone (368 μL, 5.0 mmol), andpurified by flash column chromatography (CHCl₃/MeOH=88:12 to 85:15),colorless gum, 27 mg, 25%. Compound 3aa is a known compound.

R_(f)=0.37 (CH₂Cl₂/MeOH=5:1). ¹H NMR (400 MHz, CD₃OD): δ 3.78 (dd,J=12.0 Hz, 1.7 Hz, 1H), 3.66 (td, J=9.2 Hz, 2.9 Hz, 1H), 3.61 (dd,J=12.0 Hz, 5.0 Hz, 1H), 3.36-3.29 (m, 1H), 3.28-3.20 (m, 2H), 3.06 (t,J=9.2 Hz, 1H), 2.88 (dd, J=16.0 Hz, 2.9 Hz, 1H), 2.59 (dd, J=16.0 Hz,9.2 Hz, 1H), 2.20 (s, 3H). ¹³C NMR (100 MHz, CD₃OD): δ 210.2, 81.6,79.6, 77.2, 75.1, 71.7, 62.8, 47.1, 30.6. HRMS (ESI): calcd for C₉ H₁₇O₆([M+H]⁺) 221.1020, found 221.1023.

Compound 3aa was also synthesized using pyrolidine (0.5 equiv) and boricacid (1.0 equiv). To a mixture of pyrrolidine (28.0 μL, 0.34 mmol) inDMSO (1.0 mL), acetone (1.0 mL, 13.6 mmol) and boric acid (42.0 mg, 0.68mmol) were added at room temperature (25° C.), and the mixture wasstirred for 5 min. To this mixture, glucose (150 mg, 0.68 mmol) wasadded and the mixture was stirred at the same temperature for 24 h. Themixture was purified by silica gel flash column chromatography(CH₂Cl₂/MeOH=86:14 to 78:22) to give 3aa (19.1 mg, 12%) with the5-membered ring isomers and the further cyclized forms through hemiketalformation.

Compound 3aa was also synthesized using using L-proline andtriethylamine. To a mixture of L-proline (192 mg, 1.67 mmol) in PEG (5.0mL), acetone (4.90 mL, 66.6 mmol) and triethylamine (116 μL, 0.833 mmol)were added at room temperature (25° C.), and the mixture was stirred for5 min. To this mixture, glucose (600 mg, 3.33 mmol) was added and themixture was stirred at the same temperature for 24 h. The mixture waspurified by silica gel flash column chromatography (CH₂Cl₂/MeOH=86:14 to78:22) to give a mixture of product including 3aa with the 5-memberedring isomers and further cyclized forms through hemiketal formation(93.0 mg, 88%). Based on further purification by silica gel flash columnchromatography (CH₂Cl₂/MeOH=86:14 to 78:22) and ¹H NMR analyses offractions containing 3aa, the yield of 3aa was estimated to be 18%.

Compound 3ab was synthesized by the general procedure from D-glucose (90mg, 0.50 mmol) and ethyl 5-oxohexanoate (320 μL, 2.0 mmol), and purifiedby flash column chromatography (CH₂Cl₂/MeOH=88:12 to 80:20), pale yellowgum, 59 mg, 37%.

Rf=0.25 (CH₂Cl₂/MeOH=5:1). ¹H NMR (400 MHz, CD₃OD): δ 4.08 (q, J=7.2 Hz,2H), 3.75 (dd, J=11.9 Hz, 2.2 Hz, 1H), 3.63 (td, J=9.2 Hz, 2.8 Hz, 1H),3.59 (dd, J=11.9 Hz, 5.8 Hz, 1H), 3.33-3.28 (m, 1H), 3.25 (dd, J=9.2 Hz,9.0 Hz, 1H), 3.21-3.16 (m, 1H), 3.04 (t, J=9.2 Hz, 1H), 2.81 (dd, J=15.6Hz, 2.8 Hz, 1H), 2.60-2.52 (m, 3H), 2.30 (t, J=7.2 Hz, 2H), 1.81 (quint,J=7.2 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H). ¹³C NMR (100 MHz, CD₃OD): δ211.1, 175.1, 81.6, 79.6, 77.3, 75.1, 71.6, 62.7, 61.4, 46.4, 43.0,34.0, 19.7, 14.5. HRMS (ESI): calcd for C₁₄H₂₅O₈ ([M+H]⁺) 321.1544,found 321.1543.

Compound 3ac was synthesized the general procedure from D-glucose (90mg, 0.50 mmol) and acetophenone (233 μL, 2.0 mmol), and purified byflash column chromatography (CH₂Cl₂/MeOH=86:14 to 80:20), pale yellowgum, 24 mg, 17%. Compound 3ac is a known compound.

Rf=0.29 (CH₂Cl₂/MeOH=5:1). ¹H NMR (400 MHz, CD₃OD): δ 8.01-7.99 (m, 2H),7.60 (tt, J=7.4 Hz, 1.2 Hz, 1H), 7.52-7.47 (m, 2H), 3.86 (td, J=9.0 Hz,2.5 Hz, 1H), 3.74 (dd, J=11.9 Hz, 2.4 Hz, 1H), 3.61 (dd, J=11.9 Hz, 5.0Hz, 1H), 3.42 (dd, J=16.4 Hz, 2.5 Hz, 1H), 3.41-3.30 (m, 2H), 3.25-3.17(m, 3H). ¹³C NMR (100 MHz, CD₃ OD): δ 200.6, 138.5, 134.3, 129.7, 129.3,81.5, 79.7, 77.3, 75.1, 71.6, 62.7, 42.4. HRMS (ESI): calcd for C₁₄H₁₉O₆([M+H]⁺) 283.1176, found 283.1176.

Compound 3bb was synthesized the general procedure from D-mannose (90mg, 0.50 mmol) and ethyl 5-oxohexanoate (320 μL, 2.0 mmol), and purifiedby flash column chromatography (CH₂Cl₂/MeOH=88:12 to 80:20), pale yellowgum, 32 mg, 20%.

Rf=0.27 (CH₂Cl₂/MeOH=5:1). ¹H NMR (400 MHz, CD₃OD): δ 4.11 (q, J=7.2 Hz,2H), 3.92 (ddd, J=7.6 Hz, 5.3 Hz, 0.9 Hz, 1H), 3.80 (dd, J=11.8 Hz, 2.4Hz, 1H), 3.72 (dd, J=3.2 Hz, 0.8 Hz, 1H), 3.65 (dd, J=11.8 Hz, 5.6 Hz,1H), 3.54 (t, J=9.4 Hz, 1H), 3.48 (dd, J=9.4 Hz, 3.2 Hz, 1H), 3.18 (ddd,J=9.4 Hz, 5.6 Hz, 2.4 Hz, 1H), 2.87 (dd, J=16.6 Hz, 7.6 Hz, 1H), 2.65(dd, J=16.6 Hz, 5.3 Hz, 1H), 2.58 (t, J=7.2 Hz, 2H), 2.33 (t, J=7.2 Hz,2H), 1.84 (quint, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H). ¹³C NMR (100MHz, CD₃OD): δ 210.5, 175.1, 82.0, 76.3, 75.7, 72.4, 68.5, 62.9, 61.4,44.9, 42.9, 34.1, 19.8, 14.5. HRMS (ESI): calcd for C₁₄H₂₄O₈Na ([M+Na]⁺)343.1363, found 343.1364.

2. C-Glycosidation of Di- and Trisaccharide Aldopyranoses (Schemes 1 and2) Procedures for the Synthesis of C-glycosides 5 and 7 Procedure A

To a solution of pyrrolidine (0.15 mmol, 0.5 equiv) in DMSO (1.0 mL),acetone (5.8 mmol, 20 equiv) and boric acid (0.29 mmol, 1.0 equiv) wereadded at room temperature (25° C.) and the mixture was stirred for 5min. To this mixture, carbohydrate (0.28-0.29 mmol, 1.0 equiv) was addedand the mixture was stirred at the same temperature for 24 h. Themixture was purified by silica gel flash column chromatography(CH₂Cl₂/MeOH) to give the corresponding C-glycoside 5 or 7.

Procedure B

To a solution of pyrrolidine (0.15 mmol, 0.5 equiv) in DMSO (0.35 mL),acetone (5.8 mmol, 20 equiv) and boric acid (0.29 mmol, 1.0 equiv) wereadded at room temperature (25° C.) and the mixture was stirred for 5min. To this mixture, carbohydrate (0.28-0.29 mmol, 1.0 equiv) was addedand the mixture was stirred at the same temperature for 96 h. Themixture was purified by silica gel flash column chromatography(CH₂Cl₂/MeOH) to give the corresponding C-glycoside 5 or 7.

Procedure C

A mixture of carbohydrate (0.50 mmol, 1.0 equiv) and ketone (2.0 mmol,4.0 equiv) in DMSO (1.0 mL) was stirred at room temperature (25° C.) for5 min to solubilize the carbohydrate. To the solution, pyrrolidine (0.25mmol, 0.5 equiv) and boric acid (1.0 mmol, 2.0 equiv) were added and themixture was stirred at the same temperature for 48 h. The mixture waspurified by silica gel flash column chromatography (CH₂Cl₂/MeOH) to givethe corresponding C-glycoside 5 or 7.

Compound 5aa was synthesized by procedure A from D-lactose and acetone.To a solution of pyrrolidine (12.0 μL, 0.146 mmol) in DMSO (1.0 mL),acetone (429 μL, 5.84 mmol) and boric acid (18.0 mg, 0.292 mmol) wereadded at room temperature (25° C.) and the mixture was stirred for 5min. To this mixture, D-lactose monohydrate (100 mg, 0.278 mmol) wasadded and the mixture was stirred at the same temperature for 24 h. Themixture was purified by silica gel flash column chromatography(CH₂Cl₂/MeOH=71:29 to 63:37) to give 5aa (48.1 mg, 45%, dr>10:1) as acolorless solid. Compound 5aa is a known compound.

Compound 5aa was also synthesized by procedure B. To a solution ofpyrrolidine (12.0 μL, 0.146 mmol) in DMSO (350 μL), acetone (429 μL,5.84 mmol) and boric acid (18.0 mg, 0.292 mmol) were added at roomtemperature (25° C.) and the mixture was stirred for 5 min. To thismixture, D-lactose monohydrate (100 mg, 0.278 mmol) was added and themixture was stirred at the same temperature for 96 h. The mixture waspurified by silica gel flash column chromatography (CH₂Cl₂/MeOH=71:29 to63:37) to give 5aa (64.5 mg, 61%, dr>10:1) as a colorless solid.

Compound 5aa was also synthesized by procedure C but using 10 equiv ofacetone (368 μL, 5.0 mmol) from D-lactose monohydrate (180 mg, 0.50mmol), and purified by flash column chromatography (CH₂Cl₂/MeOH=70:30 to65:35), colorless solid, 57 mg, 30%.

Rf=0.28 (CH₂Cl₂/MeOH=2:1). ¹H NMR (400 MHz, CD₃OD): δ 4.36 (d, J=7.6 Hz,1H), 3.85-3.75 (m, 3H), 3.75-3.63 (m, 2H), 3.62-3.46 (m, 6H), 3.39-3.34(m, 1H), 3.15 (t, J=8.8 Hz, 1H), 2.90 (dd, J=16.4 Hz, 2.2 Hz, 1H), 2.61(dd, J=16.4 Hz, 9.2 Hz, 1H), 2.20 (s, 3H). ¹³C NMR (100 MHz, CD₃OD): δ210.0, 105.1, 80.8, 80.2, 77.9, 77.1, 74.81, 74.78, 72.6, 70.3, 62.5,62.0, 47.0, 30.6. HRMS (ESI): calcd for C₁₅H₂₇O₁₁ ([M+H]⁺) 383.1548,found 383.1530.

Compound 5ab was synthesized by procedure C from D-lactose and ethyl5-oxohexanoate. A mixture of D-lactose monohydrate (180 mg, 0.50 mmol)and ethyl 5-oxohexanoate (320 μL, 2.0 mmol) in DMSO (1.0 mL) was stirredat room temperature (25° C.) for 5 min to solubilize the carbohydrate.To the solution, pyrrolidine (21 μL, 0.25 mmol) and H₃BO₃ (61 mg, 1.0mmol) were added and the mixture was stirred at the same temperature for48 h. The mixture was purified by silica gel flash column chromatography(CH₂Cl₂/MeOH=70:30 to 64:36) to give 5ab (109 mg, 45%, dr>20:1) as acolorless solid.

Compound 5ab was also synthesized by a modified procedure C fromD-lactose and ethyl 5-oxohexanoate with reaction time for 96 h. Amixture of D-lactose monohydrate (180 mg, 0.50 mmol) and ethyl5-oxohexanoate (320 μL, 2.0 mmol) in DMSO (1.0 mL) was stirred at roomtemperature (25° C.) for 5 min to solubilize the carbohydrate. To thesolution, pyrrolidine (21 μL, 0.25 mmol) and H3BO3 (61 mg, 1.0 mmol)were added and the mixture was stirred at the same temperature for 96 h.The mixture was purified by silica gel flash column chromatography(CHCl₃/MeOH=65:35 to 60:40) to give 5ab (156 mg, 65%, dr>10:1) as acolorless solid.

Rf=0.27 (CH₂Cl₂/MeOH=2:1). ¹H NMR (400 MHz, CD₃OD): δ 4.35 (d, J=7.5 Hz,1H), 4.11 (q, J=7.1 Hz, 2H), 3.82-3.75 (m, 4H), 3.72-3.65 (m, 2H),3.60-3.46 (m, 5H), 3.36-3.32 (m, 1H), 3.14 (dd, J=9.4 Hz, 8.8 Hz, 1H),2.85 (dd, J=15.7 Hz, 2.9 Hz, 1H), 2.62-2.56 (m, 3H), 2.32 (t, J=7.2 Hz,2H), 1.84 (quint, J=7.2 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H). ¹³C NMR (100MHz, CD₃OD): δ 211.0, 175.1, 105.0, 80.8, 80.1, 77.9, 77.2, 77.0, 74.8,72.5, 70.2, 62.4, 61.9, 61.4, 46.3, 43.1, 34.0, 19.8, 14.5. HRMS (ESI):calcd for C₂₀H₃₅O₁₃ ([M+H]⁺) 483.2072, found 483.2062.

Compound 5ac was synthesized by procedure C from D-lactose monohydrate(180 mg, 0.50 mmol) and acetophenone (233 μL, 2.0 mmol), and purified byflash column chromatography (CH₂Cl₂/MeOH=74:26 to 65:35), colorlesssolid, 80 mg, 36%, dr>10:1.

Rf=0.27 (CH₂Cl₂/MeOH=2:1). ¹H NMR (400 MHz, (CD₃)₂SO): δ 7.96 (d, J=7.0Hz, 2H), 7.63-7.61 (m, 1H), 7.54-7.50 (m, 2H), 5.25 (d, J=5.7 Hz, 1H),5.09 (d, J=4.1 Hz, 1H), 4.77 (d, J=4.8 Hz, 1H), 4.70 (d, J=0.9 Hz, 1H),4.64 (t, J=5.2 Hz, 1H), 4.51 (d, J=4.5 Hz, 1H), 4.37 (t, J=6.0 Hz, 1H),4.21 (d, J=7.2 Hz, 1H), 3.73 (td, J=9.3 Hz, 2.4 Hz, 1H), 3.64-3.59 (m,2H), 3.57-3.44 (m, 4H), 3.37-3.27 (m, 5H), 3.23-3.18 (m, 1H), 3.16-3.05(m, 2H). ¹³C NMR (100 MHz, (CD₃)₂SO): δ 198.0, 136.9, 133.0, 128.6,128.0, 103.8, 80.9, 78.6, 76.2, 75.57, 75.52, 73.25, 73.22, 70.5, 68.1,60.5, 60.3, 41.0. HRMS (ESI): calcd for C₂₀H₂₉O₁₁ ([M+H]⁺) 445.1704,found 445.1700.

Compound 5ad was synthesized by procedure C from D-lactose monohydrate(180 mg, 0.50 mmol) and cyclopropyl methyl ketone (198 μL, 2.0 mmol),and purified by flash column chromatography (CH₂Cl₂/MeOH=7:3 to 6:4),colorless solid, 92 mg, 45%.

Rf=0.27 (CH₂Cl₂/MeOH=2:1). ¹H NMR (400 MHz, CD₃OD): δ 4.36 (d, J=7.5 Hz,1H), 3.86-3.63 (m, 5H), 3.60-3.46 (m, 6H), 3.38-3.32 (m, 1H), 3.17 (dd,J=9.2 Hz, 8.8 Hz, 1H), 3.02 (dd, J=16.0 Hz, 2.6 Hz, 1H), 2.72 (dd,J=16.4 Hz, 9.2 Hz, 1H), 2.15-2.09 (m, 1H), 1.00-0.89 (m, 4H). ¹³C NMR(100 MHz, CD₃OD): δ 212.0, 105.0, 80.7, 80.1, 77.9, 77.0, 76.8, 74.7,74.6, 72.5, 70.2, 62.4, 61.9, 46.6, 21.7, 11.5, 11.2. HRMS (ESI): calcdfor C₁₇H₂₉O₁₁ ([M+H]⁺) 409.1704, found 409.1698.

Compound 5ae was synthesized by procedure C from D-lactose monohydrate(180 mg, 0.50 mmol) and benzyl 5-oxohexanoate (440 mg, 2.0 mmol), andpurified by flash column chromatography (CH₂Cl₂/MeOH=70:30 to 64:36),colorless gum, 95 mg, 35%.

Rf=0.27 (CH₂Cl₂/MeOH=2:1). ¹H NMR (400 MHz, CD₃OD): δ 7.36-7.30 (m, 5H),5.10 (s, 2H), 4.36 (d, J=7.6 Hz, 1H), 3.83 (dd, J=3.1 Hz, 0.7 Hz, 1H),3.81-3.65 (m, 5H), 3.62-3.48 (m, 5H), 3.36-3.32 (m, 1H), 3.16 (dd, J=9.2Hz, 8.8 Hz, 1H), 2.84 (dd, J=15.8 Hz, 2.9 Hz, 1H), 2.61-2.54 (m, 3H),2.38 (t, J=7.2 Hz, 2H), 1.85 (quint, J=7.2 Hz, 2H). ¹³C NMR (100 MHz,CD₃OD): δ 211.0, 174.7, 137.5, 129.5, 129.1, 105.0, 80.8, 80.0, 77.7,77.1, 76.9, 74.76, 74.70, 72.4, 70.2, 67.1, 62.4, 61.9, 46.2, 43.0,34.0, 19.7. HRMS (ESI): calcd for C₂₅H₃₇O₁₃ ([M+H]⁺) 545.2229, found545.2210.

Compound 5af was synthesized by procedure C, from D-lactose monohydrate(180 mg, 0.50 mmol) and 5-hexyn-2-one (192 mg, 2.0 mmol), and purifiedby flash column chromatography (CH₂Cl₂/MeOH=75:25 to 70:30), colorlesssolid, 44 mg, 21%.

Rf=0.27 (CH₂Cl₂/MeOH=2:1). ¹NMR (400 MHz, CD₃OD): δ 4.35 (d, J=7.6 Hz,1H), 3.84-3.80 (m, 3H), 3.80-3.75 (m, 1H), 3.72-3.64 (m, 2H), 3.60-3.46(m, 6H), 3.36-3.32 (m, 1H), 3.15 (dd, J=9.6 Hz, 8.8 Hz, 1H), 2.87 (dd,J=16.0 Hz, 2.8 Hz, 1H), 2.82-2.74 (m, 2H), 2.62 (dd, J=16.0 Hz, 9.1 Hz,1H), 2.39 (td, J=7.1 Hz, 2.6 Hz, 2H), 2.20 (t, J=2.6 Hz, 1H). ¹³C NMR(100 MHz, CD₃OD): δ 209.2, 105.0, 84.0, 80.7, 80.1, 77.9, 77.1, 77.0,74.8, 72.5, 70.3, 69.6, 62.5, 61.9, 46.2, 43.1, 13.3. HRMS (ESI): calcdfor C₁₈H₂₉O₁₁ ([M+H]⁺) 421.1704, found 421.1698.

Compound 5ag was synthesized by procedure C from D-lactose monohydrate(180 mg, 0.50 mmol) and 4′-methylacetophenone (267 μL, 2.0 mmol), andpurified by flash column chromatography (CH₂Cl₂/MeOH=74:26 to 65:35),colorless solid, 80 mg, 35%.

Compound 5ag was also synthesized by procedure C except that thereaction was carried out for 96 h from D-lactose monohydrate (180 mg,0.50 mmol) and 4′-methylacetophenone (267 μL, 2.0 mmol), and purified byflash column chromatography (CH₂Cl₂/MeOH=74:26 to 65:35), colorlesssolid, 126 mg, 55%.

Rf=0.27 (CH₂Cl₂/MeOH=2:1). ¹NMR (400 MHz, CD₃OD): δ 7.90 (d, J=8.0 Hz,2H), 7.31 (d, J=8.0 Hz, 2H), 4.36 (d, J=7.5 Hz, 1H), 3.86-3.73 (m, 6H),3.71 (dd, J=11.6 Hz, 4.8 Hz, 1H), 3.62-3.51 (m, 5H), 3.49 (dd, J=10.0Hz, 3,6 Hz, 1H), 3.37-3.33 (m, 1H), 3.28-3.20 (m, 1H), 2.40 (s, 3H). ¹³CNMR (100 MHz, CD₃OD): δ 200.2, 145.5, 136.0, 130.2, 129.5, 105.0, 80.7,80.1, 78.0, 77.2, 77.0, 74.79, 74.76, 72.5, 70.3, 62.5, 61.8, 42.1,21.6. HRMS (ESI): calcd for C₂₁H₃₁O₁₁ ([M+H]⁺) 459.1861, found 459.1852.

Compound 5ah was synthesized by procedure C from D-lactose monohydrate(180 mg, 0.50 mmol) and 4′-nitroacetophenone (330 mg, 2.0 mmol), andpurified by column chromatography (CH₂Cl₂/MeOH=68:32 to 60:40),colorless solid, 61 mg, 25%.

Rf=0.27 (CH₂Cl₂/MeOH=2:1). ¹NMR (400 MHz, (CD₃)₂SO): δ 8.32 (d, J=8.9Hz, 2H), 8.17 (d, J=8.9 Hz, 2H), 5.32 (d, J=5.6 Hz, 1H), 5.11 (d, J=3.7Hz, 1H), 4.81 (s, 1H), 4.73 (s, 1H), 4.68-4.67 (m, 1H), 4.55 (d, J=4.5Hz, 1H), 4.42 (t, J=5.9 Hz, 1H), 4.21 (d, J=7.3 Hz, 1H), 3.70 (td, J=9.1Hz, 2.7 Hz, 1H), 3.65-3.58 (m, 2H), 3.57-3.44 (m, 4H), 3.41-3.28 (m,5H), 3.23-3.15 (m, 2H), 3.13-3.06 (m, 1H). ¹³C NMR (100 MHz, (CD₃)₂SO):δ 197.6, 149.8, 141.7, 129.5, 123.8, 103.8, 80.8, 78.7, 76.1, 75.6,75.5, 73.3, 73.2, 70.6, 68.1, 60.5, 60.3, 41.8. HRMS (ESI): calcd forC₂₀H₂₈NO₁₃ ([M+H]⁺) 490.1555, found 490.1557.

Compound 5ba was synthesized by a modified procedure A from D-maltosemonohydrate and acetone. To a solution of pyrrolidine (11.0 μL. 0.134mmol) in DMSO (1.0 mL), acetone (408 μL, 5.55 mmol) and boric acid (17.0mg, 0.277 mmol) were added at room temperature (25° C.) and the mixturewas stirred for 5 min. To this mixture, D-maltose monohydrate (100 mg,0.277 mmol) was added and the mixture was stirred at the sametemperature for 96 h. The mixture was purified by silica gel flashcolumn chromatography (CH₂Cl₂/MeOH=70:30 to 63:37) to give 5ba (49.1 mg,46%, dr>10:1) as a pale yellow gum. Compound 5ba is a known compound.

Rf=0.38 (CH₂Cl₂/MeOH=2:1). ¹NMR (400 MHz, CD₃OD): δ 5.16 (d, J=3.6 Hz,1H), 3.86-3.74 (m, 3H), 3.72-3.58 (m, 5H), 3.52 (t, J=9.2 Hz, 1H), 3.45(dd, J=9.8 Hz, 3.8 Hz, 1H), 3.35-3.24 (m, 2H), 3.13 (t, J=9.2 Hz, 1H),2.88 (dd, J=16.0 Hz, 2.8 Hz, 1H), 2.61 (dd, J=16.0 Hz, 9.0 Hz, 1H), 2.21(s, 3H). ¹³C NMR (100 MHz, CD₃OD): δ 210.2, 102.8, 81.4, 80.3, 79.4,77.2, 75.0, 74.69, 74.66, 74.2, 71.5, 62.7, 62.2, 47.0, 30.6. HRMS(ESI): calcd for C₁₅H₂₇O₁₁ ([M+H]⁺) 383.1548, found 383.1538.

Compound 5ca was synthesized by procedure A from D-cellobiose andacetone. To a solution of pyrrolidine (12.0 μL, 0.146 mmol) in DMSO (1.0mL), acetone (429 μL, 5.84 mmol) and boric acid (18.0 mg, 0.292 mmol)were added at room temperature (25° C.) and the mixture was stirred for5 min. To this mixture, D-cellobiose (100 mg, 0.292 mmol) was added andthe mixture was stirred at the same temperature for 48 h. The mixturewas purified by silica gel flash column chromatography(CH₂Cl₂/MeOH=76:24 to 66:34) to give 5ca (58.7 mg, 53%, dr>10:1) as apale yellow solid. Compound 5ca is a known compound.

Rf=0.43 (CH₂Cl₂/MeOH=2:1). NMR (400 MHz, CD₃OD): δ 4.10 (d, 1H, J=8.0Hz), 3.88 (dd, J=11.6 Hz, 2.0 Hz, 1H), 3.85-3.78 (m, 2H), 3.72-3.63 (m,2H), 3.54 (t, J=9.0 Hz, 2H), 3.49 (t, J=8.6 Hz, 1H), 3.41-3.28 (m, 4H),3.24 (dd, J=8.8 Hz, 8.0 Hz, 1H), 3.15 (dd, J=9.2 Hz, 8.8 Hz, 1H), 2.89(dd, J=16.4 Hz, 2.8 Hz, 1H), 2.61 (dd, J=16.4 Hz, 9.2 Hz, 1H), 2.20 (s,3H). ¹³C NMR (100 MHz, CD₃OD): δ 210.4, 104.5, 80.8, 80.1, 78.0, 77.8,77.7, 76.9, 74.9, 74.8, 71.3, 62.4, 61.9, 47.0, 30.7. HRMS (ESI): calcdfor C₁₅H₂₇O₁₁ ([M+H]⁺) 383.1548, found 383.1548.

Compound 7aa was synthesized by a modified procedure C from3′-sialyllactose sodium salt and acetone. To a solution of pyrrolidine(13.0 μL, 0.158 mmol) in DMSO (370 μL), acetone (448 μL, 6.09 mmol) andboric acid (38.0 mg, 0.614 mmol) were added at room temperature (25° C.)and the mixture was stirred for 5 min. To this mixture, 3′-sialyllactosesodium salt (200 mg, 0.305 mmol) was added and the mixture was stirredat the same temperature for 96 h. The mixture was purified by silica gelflash column chromatography (CH₂Cl₂/MeOH=61:39 to 45:55) to give 7aa(151.4 mg, 74%, dr>10:1) as a pale yellow gum.

Rf=0.53 (CH₂Cl₂/MeOH=1:1). ¹H NMR (400 MHz, CD₃OD): δ 4.43 (d, J=7.6 Hz,1H), 4.05 (dd, J=9.6 Hz, 3.2 Hz, 1H), 3.95-3.91 (m, 1H), 3.89-3.47 (m,16H), 3.39-3.34 (m, 1H), 3.14 (t, J=9.0 Hz, 1H), 2.89 (dd, J=16.0 Hz,2.8 Hz, 1H), 2.86 (d, J=12.4 Hz, 4.0 Hz, 1H), 2.61 (dd, J=16.0 Hz, 9.2Hz, 1H), 2.20 (s, 3H), 2.01 (s, 3H), 1.79-1.68 (m, 1H). ¹³C NMR (100MHz, CD₃OD) δ 210.2, 175.5, 174.9, 105.1, 101.1, 81.3, 80.2, 77.8, 77.6,77.2, 77.0, 74.9, 74.8, 73.0, 70.8, 70.1, 69.4, 69.0, 64.6, 62.7, 62.2,54.0, 47.1, 42.1, 30.6, 22.6. HRMS (ESI): calcd for C₂₆H₄₄NO₁₉ ([M+H]⁺)674.2502, found 674.2493.

Compound 7ab was synthesized by procedure C except that the reaction wascarried out in a 0.25 mmol-scale and for 42 h from 3′-sialyllactosesodium salt (164 mg, 0.25 mmol) and ethyl 5-oxohexanoate (160 μL, 1.0mmol), and purified by column chromatography (CHCl₃/MeOH=45:55 to30:70), colorless gum, 80 mg, 40%.

Rf=0.27 (CH₂Cl₂/MeOH=1:1). ¹H NMR (400 MHz, CD₃OD): δ 4.42 (d, J=7.9 Hz,1H), 4.11 (q, J=7.1 Hz, 2H), 4.04 (dd, J=9.7 Hz, 3.1 Hz, 1H), 3.92 (brd,J=2.8 Hz, 1H), 3.87-3.55 (m, 14H), 3.53-3.47 (m, 2H), 3.37-3.33 (m, 1H),3.14 (t, J=9.1 Hz, 1H), 2.87-2.80 (m, 2H), 2.67-2.53 (m, 3H), 2.32 (t,J=7.1 Hz, 2H), 2.01 (s, 3H), 1.84 (quint, J=7.1 Hz, 2H), 1.77-1.69 (m,1H), 1.24 (t, J=7.1 Hz, 3H). ¹³C NMR (100 MHz, CD₃OD): δ 211.1, 175.4,175.1, 174.9, 105.0, 101.0, 81.0, 80.1, 77.7, 77.5, 77.2, 76.9, 74.9,74.8, 72.9, 70.7, 70.0, 69.2, 68.9, 64.4, 62.6, 62.0, 61.4, 53.9, 46.3,43.1, 42.0, 34.0, 22.6, 19.7, 14.5. HRMS (ESI): calcd for C₃₁H₅₂O₂₁N([M+H]⁺) 774.3026, found 774.3020.

Compound 7ba was synthesized by a modified procedure C from6′-sialyllactose sodium salt and acetone. To a solution of pyrrolidine(13.0 μL, 0.158 mmol) in DMSO (370 μL), acetone (448 μL, 6.09 mmol) andboric acid (38.0 mg, 0.614 mmol) were added at room temperature (25° C.)and the mixture was stirred for 5 min. To this mixture, 6′-sialyllactosesodium salt (200 mg, 0.305 mmol) was added and the mixture was stirredat the same temperature for 96 h. The mixture was purified by silica gelflash column chromatography (CH₂Cl₂/MeOH=54:46 to 33:67) to give 7ba(164.4 mg, 80%, dr>10:1) as a pale yellow gum.

Rf=0.23 (CH₂Cl₂/MeOH=1:1). ¹H NMR (400 MHz, CD₃OD): δ 4.33 (d, J=7.2 Hz,1H), 4.06 (dd, J=9.8 Hz, 7.8 Hz, 1H), 3.94-3.46 (m, 17H), 3.42-3.36 (m,1H), 3.24-3.17 (m, 1H), 2.93 (dd, J=16.0, 2.8 Hz, 1H), 2.80 (dd, J=12.0Hz, 4.4 Hz, 1H), 2.63 (dd, J=16.0 Hz, 8.8 Hz, 1H), 2.21 (s, 3H), 2.01(s, 3H), 1.66 (t, J=12.0 Hz, 1H). ¹³C NMR (100 MHz, CD₃OD) δ 210.3,175.0, 174.6, 105.2, 101.5, 81.8, 80.1, 77.8, 76.8, 75.7, 75.0, 74.7,74.2, 73.2, 72.4, 70.6, 70.3, 69.7, 64.63, 64.55, 62.2, 53.9, 47.0,42.3, 30.7, 22.9. HRMS (ESI): calcd for C₂₆H₄₄NO₁₉ ([M+H]⁺) 674.2502,found 674.2491.

Compound 7ca was synthesized by a modified procedure A fromD-maltotriose and acetone. To a solution of pyrrolidine (8.0 μL, 0.097mmol) in DMSO (1.0 mL), acetone (292 μL, 3.97 mmol) and boric acid (12.0mg, 0.194 mmol) were added at room temperature (25° C.) and the mixturewas stirred for 5 min. To this mixture, D-maltotriose (100 mg, 0.198mmol) was added and the mixture was stirred at the same temperature for96 h. The mixture was purified by silica gel flash column chromatography(CH₂Cl₂/MeOH=70:30 to 63:37) to give 7ca (37.9 mg, 35%, dr>10:1) as apale yellow gum.

Rf=0.20 (CH₂Cl₂/MeOH=2:1). ¹H NMR (400 MHz, CD₃OD): δ 5.165 (d, J=3.6Hz, 1H), 5.159 (d, J=3.6 Hz, 1H), 3.90-3.59 (m, 12H), 3.54-3.43 (m, 4H),3.35-3.24 (m, 2H), 3.13 (t, J=9.4 Hz, 1H), 2.88 (dd, J=16.2 Hz, 2.8 Hz,1H), 2.61 (dd, J=16.2 Hz, 9.2 Hz, 1H), 2.21 (s, 3H). ¹³C NMR (100 MHz,CD₃OD): δ 210.2, 102.8, 102.6, 81.4, 81.2, 80.2, 79.3, 77.2, 75.0, 74.9,74.71, 74.65, 74.2, 73.8, 73.3, 71.4, 62.7, 62.3, 62.1, 47.0, 30.7. HRMS(ESI): calcd for C₂₁H₃₇O₁₆ ([M+H]⁺) 545.2076, found 545.2067.

Compound 7cc was synthesized by procedure C except that the reaction wascarried out in a 0.25 mmol-scale from D-maltotriose (126 mg, 0.25 mmol)and acetophenone (117 μL, 1.0 mmol), and purified by flash columnchromatography (CH₂Cl₂/MeOH=60:40 to 50:50), colorless gum, 33 mg, 22%.

Rf=0.27 (CH₂Cl₂/MeOH=1:1). ¹H NMR (400 MHz, CD₃OD): δ 8.01 (d, J=7.2 Hz,2H), 7.60 (tt, J=7.4Hz, 1.2 Hz, 1H), 7.49 (t, J=7.4 Hz, 2H), 5.18 (d,J=4.0 Hz, 1H), 5.16 (d, J=3.7 Hz, 1H), 3.91-3.80 (m, 5H), 3.79-3.73 (m,3H), 3.72-3.43 (m, 9H), 3.41-3.19 (m, 4H). ¹³C NMR (100 MHz, CD₃OD): δ200.5, 138.5, 134.3, 129.7, 129.3, 102.8, 102.6, 81.4, 81.2, 80.1, 79.4,77.2, 75.0, 74.9, 74.7, 74.6, 74.2, 73.8, 73.2, 71.4, 62.7, 62.1, 42.2.HRMS (ESI): calcd for C₂₆H₃₉O₁₆ ([M+H]⁺) 607.2233, found 607.2216.

Compound 7cd was synthesized by procedure C except that the reaction wascarried out in a 0.25 mmol-scale from D-maltotriose (126 mg, 0.25 mmol)and cyclopropyl methyl ketone (100 μL, mmol), and purified by flashcolumn chromatography (CH₂ Cl₂/MeOH=65:35 to 50:50), colorless gum, 42mg, 30%.

Rf=0.27 (CH₂Cl₂/MeOH=1:1). ¹H NMR (400 MHz, CD₃OD): δ 5.19-5.15 (m, 2H),3.89-3.81 (m, 4H), 3.81-3.60 (m, 8H), 3.58-3.44 (m, 4H), 3.35-3.25 (m,2H), 3.16 (td, J=9.0 Hz, 2.4 Hz, 1H), 3.02 (d, J=16.2 Hz, 1H), 2.76-2.69(m, 1H), 2.15-2.09 (m, 1H), 0.98-0.93 (m, 4H). ¹³C NMR (100 MHz, CD₃OD):δ 212.1, 102.7, 102.6, 81.3, 81.2, 80.1, 79.3, 76.9, 75.0, 74.9, 74.7,74.5, 74.1, 73.7, 73.2, 71.4, 62.6, 62.1, 62.0, 46.6, 21.7, 11.6, 11.3.HRMS (ESI): calcd for C₂₃H₃₉O₁₆ ([M+H]⁺) 571.2233, found 571.2231.

Compound 7cg was synthesized by procedure C except that the reaction wascarried out in a 0.25 mmol-scale from D-maltotriose (126 mg, 0.25 mmol)and 4′-methylacetophenone (134 μL, 1.0 mmol), and purified by flashcolumn chromatography (CH₂Cl₂/MeOH=60:40 to 50:50), colorless gum, 39mg, 25%.

Rf=0.27 (CH₂Cl₂/MeOH=1:1). ¹H NMR (400 MHz, CD₃OD): δ 7.90 (d, J=8.0 Hz,2H), 7.31 (d, J=8.0 Hz, 2H), 5.17 (d, J=3.8 Hz, 1H), 5.15 (d, J=3.8 Hz,1H), 3.91-3.80 (m, 5H), 3.78-3.72 (m, 3H), 3.70-3.67 (m, 2H), 3.66-3.63(m, 1H), 3.63-3.56 (m, 2H), 3.54-3.52 (m, 1H), 3.51-3.48 (m, 1H), 3.45(dd, J=9.7 Hz, 3.7 Hz, 1H), 3.39 (dd, J=16.4 Hz, 2.3 Hz, 1H), 3.34-3.31(m, 1H), 3.30-3.23 (m, 2H), 3.19 (dd, J=16.4 Hz, 8.9 Hz, 1H), 2.40 (s,3H). ¹³C NMR (100 MHz, CD₃OD): δ 200.2, 145.5, 135.9, 130.3, 129.5,102.8, 102.6, 81.4, 81.3, 80.1, 79.4, 77.2, 75.0, 74.9, 74.7, 74.6,74.2, 73.8, 73.2, 71.5, 62.6, 62.13, 62.10, 42.1, 21.6. HRMS (ESI):calcd for C₂₇H₄₁O₁₆ ([M+H]⁺) 621.2389, found 621.2374.

Compound 7ci was synthesized by procedure C except that the reaction wascarried out in a 0.25 mmol-scale from D-maltotriose (126 mg, 0.25 mmol)and 4′-cyanoacetophenone (145 mg, 1.0 mmol), and purified by flashcolumn chromatography (CH₂Cl₂/MeOH=60:40 to 49:51), colorless gum, 35mg, 22%.

Rf=0.27 (CH₂Cl₂/MeOH=1:1). ¹H NMR (400 MHz, CD₃OD): δ 8.08 (d, J=8.2 Hz,2H), 7.81 (d, J=8.2 Hz, 2H), 5.14-5.11 (m, 2H), 3.85-3.76 (m, 5H),3.73-3.66 (m, 3H), 3.64-3.54 (m, 5H), 3.52-3.35 (m, 5H), 3.26-3.21 (m,3H). ¹³C NMR (100 MHz, CD₃OD): δ 199.2, 141.6, 133.6, 129.9, 118.9,117.1, 102.7, 102.5, 81.2, 81.1, 80.1, 79.3, 77.0, 74.9, 74.8, 74.6,74.5, 74.0, 73.7, 73.1, 71.3, 62.5, 62.08, 62.04, 42.2. HRMS (ESI):calcd for C₂₇H₃₈NO₁₆ ([M+H]⁺) 632.2185, found 632.2174.

3. Transformations of the C-Glycoside Ketones (Schemes 3, 4, and 5)Compound 8a

To a mixture of L-proline (8.0 mg, 0.069 mmol) in DMSO (0.5 mL),6-methoxy-2-napthaldehyde (24.4 mg, 0.131 mmol) andN,N-diisopropylethylamine (11.0 μL, 0.063 mmol) were added at roomtemperature (25° C.), and the mixture was stirred for 5 min. To thismixture, compound 5aa (50.0 mg, 0.131 mmol) was added and the mixturewas stirred at the same temperature for 96 h. The mixture was purifiedby silica gel flash column chromatography (CH₂Cl₂/MeOH=86:14 to 79:21)to give 8a (38.0 mg, 53%) as a pale yellow solid.

To a solution of pyrrolidine (5.0 μL, 0.061 mmol) in DMSO (1.0 mL),6-methoxy-2-naphthaldehyde (24.4 mg, 0.131 mmol) and boric acid (4.0 mg,0.065 mmol) were added at room temperature (25° C.) and the mixture wasstirred for 5 min. To this mixture, compound 5aa (50.0 mg, 0.131 mmol)was added and the mixture was stirred at the same temperature for 96 h.The mixture was purified by silica gel flash column chromatography((CH₂Cl₂/MeOH=86:14 to 79:21) to give 8a (27.3 mg, 38%) as a pale yellowsolid.

Rf=0.32 (CH₂Cl₂/MeOH=4:1). ¹H NMR (400 M Hz, CD₃OD): δ 7.98 (s, 1H),7.82-7.71 (m, 4H), 7.24 (d, J=2.4 Hz, 1H), 7.15 (dd, J=9.0 Hz, 2.6 Hz,1H), 6.96 (d, J=16.4 Hz, 1H), 4.39 (d, J=7.2 Hz, 1H), 3.91 (s, 3H),3.91-3.45 (m, 11H), 3.43-3.37 (m, 1H), 3.31-3.25 (m, 1H), 3.17 (dd,J=16.0 Hz, 2.4 Hz, 1H), 2.96 (dd, J=16.0 Hz, 8.8 Hz, 1H). ¹³C NMR (100MHz, CD₃OD) δ 201.1, 160.5, 145.5, 137.5, 131.7, 131.23, 131.16, 130.1,128.7, 126.5, 125.2, 120.5, 107.1, 105.1, 80.8, 80.1, 77.9, 77.3, 77.0,74.8, 74.7, 72.5, 70.3, 62.5, 61.9, 55.9, 44.1. HRMS (ESI): calcd forC₂₇H₃₅O₁₂ ([M+H]⁺) 551.21230, found 551.21002.

Compound 8b

To a solution of pyrrolidine (5.0 μL, 0.061 mmol) in DMSO (1.0 mL),6-methoxy-2-napthaldehyde (24.4 mg, 0.131 mmol) and boric acid (4.0 mg,0.065 mmol) were added at room temperature (25° C.) and the mixture wasstirred for 5 min. To this mixture, compound 5ba (50.0 mg, 0.131 mmol)was added and the mixture was stirred at the same temperature for 96 h.The mixture was purified by silica gel flash column chromatography(CH₂Cl₂/MeOH=90:10 to 82:18) to give 8b (30.1 mg, 42%) as a pale yellowgum.

Rf=0.47 (CH₂Cl₂/MeOH=4:1). ¹H NMR (400 MHz, CD₃OD): δ 8.00 (s, 1H),7.82-7.77 (m, 2H), 7.80 (d, J=16.4 Hz, 1H), 7.74 (dd, J=8.8 Hz, 1.6 Hz,1H), 7.25 (d, J=2.0 Hz, 1H), 7.16 (dd, J=8.8 Hz, 2.6 Hz, 1H), 6.97 (d,J=16.4 Hz, 1H), 5.18 (d, J=4.0 Hz, 1H), 3.92 (s, 3H), 3.86-3.75 (m, 4H),3.75-3.53 (m, 5H), 3.46 (dd, J=9.2 Hz, 4.0 Hz, 1H), 3.37-3.31 (m, 1H),3.30-3.22 (m, 2H), 3.16 (dd, J=15.6 Hz, 2.6 Hz, 1H), 2.95 (dd, J=15.6Hz, 9.2 Hz, 1H). ¹³C NMR (100 MHz, CD₃OD) δ 201.1, 160.6, 145.5, 137.6,131.6, 131.3, 130.2, 128.7, 126.5, 125.3, 120.5, 107.2, 102.9, 81.5,80.3, 79.5, 77.6, 75.1, 74.81, 74.75, 74.3, 71.1, 62.8, 62.2, 55.9,44.3. HRMS (ESI): calcd for C₂₇H₃₅O₁₂ ([M+H]⁺) 551.21230, found551.21008.

Compound 8c

To a mixture of L-proline (8.0 mg, 0.069 mmol) in DMSO (1.0 mL),6-methoxy-2-napthaldehyde (24.0 mg, 0.129 mmol) andN,N-diisopropylethylamine (11.0 μL, mmol) were added at room temperature(25° C.), and the mixture was stirred for 5 min. To this mixture,compound 5ca (50.0 mg, 0.131 mmol) was added and the mixture was stirredat the same temperature for 96 h. The mixture was purified by silica gelflash column chromatography (CH₂Cl₂/MeOH=86:14 to 79:21) to give 8c(19.0 mg, 27%) as a pale yellow solid.

Rf=0.66 (CH₂Cl₂/MeOH=4:1). ¹H NMR (400 MHz, CD₃OD): δ 7.99 (s, 1H),7.81-7.77 (m, 2H), 7.80 (d, J=16.2 Hz, 1H), 7.74 (dd, J=8.8 Hz, 1.6 Hz,1H), 7.25 (d, J=2.4 Hz, 1H), 7.16 (dd, J=8.8 Hz, 2.4 Hz, 1H), 6.97 (d,J=16.2 Hz, 1H), 4.43 (d, J=8.0 Hz, 1H), 3.92 (s, 3H), 3.92-3.77 (m, 4H),3.68 (dd, J=12.0 Hz, 5.6 Hz, 1H), 3.60 (t, J=8.8 Hz, 1H), 3.54 (t, J=8.8Hz, 1H), 3.41-3.31 (m, 4H), 3.30-3.21 (m, 2H), 3.15 (dd, J=15.8 Hz, 2.6Hz, 1H), 2.96 (dd, J=15.8 Hz, 9.0 Hz, 1H). ¹³C NMR (100 MHz, CD₃OD) δ201.1, 160.6, 145.5, 137.6, 131.7, 131.3, 131.2, 130.2, 128.7, 126.5,125.3, 120.5, 107.1, 104.6, 80.8, 80.2, 78.1, 78.0, 77.8, 77.4, 74.9,71.4, 62.4, 61.9, 55.9, 44.2. HRMS (ESI): calcd for C₂₇H₃₅O₁₂ ([M+H]⁺)551.21230, found 551.21227.

Compound 8d

To a solution of pyrrolidine (3.0 μL, 0.037 mmol) in DMSO (1.0 mL),6-methoxy-2-napthaldehyde (14.0 mg, 0.075 mmol) and boric acid (5.0 mg,0.081 mmol) were added at room temperature (25° C.) and the mixture wasstirred for 5 min. To this mixture, compound 7aa (50.0 mg, 0.074 mmol)was added and the mixture was stirred at the same temperature for 48 h.The mixture was purified by silica gel flash column chromatography(CH₂Cl₂/MeOH=69:31 to 51:49) to give 8d (24.6 mg, 40%) as a pale yellowsolid.

Rf=0.16 (CH₂Cl₂/MeOH=2:1). ¹H NMR (400 MHz, CD₃OD): δ 7.99 (s, 1H),7.82-7.76 (m, 2H), 7.80 (d, J=16.0 Hz, 1H), 7.74 (dd, J=8.8 Hz, 1.6 Hz,1H), 7.25 (d, 1H, J=2.4 Hz), 7.16 (dd, J=8.8 Hz, 2.4 Hz, 1H), 6.96 (d,J=16.0 Hz, 1H), 4.45 (d, J=8.0 Hz, 1H), 4.06 (dd, J=9.6 Hz, 3.2 Hz, 1H),3.94-3.46 (m, 17H), 3.92 (s, 3H), 3.42-3.37 (m, 1H), 3.26 (dd, J=9.6 Hz,8.8 Hz, 1H), 3.15 (dd, J=15.6 Hz, 2.4 Hz, 1H), 2.95 (dd, J=15.6 Hz, 9.0Hz, 1H), 2.89-2.83 (m, 1H), 2.01 (s, 3H), 1.79-1.68 (m, 1H). ¹³C NMR(100 MHz, CD₃OD) δ 201.1, 175.5, 174.9, 160.6, 145.4, 137.5, 131.6,131.2, 130.2, 128.7, 126.5, 125.3, 120.5, 107.1, 105.0, 101.1, 81.1,80.2, 77.9, 77.6, 77.5, 77.0, 74.9, 74.8, 73.0, 70.8, 70.1, 69.3, 69.0,64.5, 62.7, 62.0, 55.9, 53.9, 44.2, 42.1, 22.6. HRMS (ESI): calcd forC₃₈H₅₂NO₂₀([M+H]⁺) 842.3077, found 842.3051.

Compound 8e

To a solution of pyrrolidine (3.0 μL, 0.037 mmol) in DMSO (1.0 mL),6-methoxy-2-napthaldehyde (14.0 mg, 0.075 mmol) and boric acid (5.0 mg,0.081 mmol) were added at room temperature (25° C.) and the mixture wasstirred for 5 min. To this mixture, compound 7ba (50.0 mg, 0.074 mmol)was added and the mixture was stirred at the same temperature for 48 h.The mixture was purified by silica gel flash column chromatography(CH₂Cl₂/MeOH=69:31 to 51:49) to give 8e (21.5 mg, 35%) as a pale yellowsolid.

Rf=0.16 (CH₂Cl₂/MeOH=2:1). ¹H NMR (400 MHz, CD₃OD): δ 7.99 (s, 1H),7.82-7.72 (m, 3H), 7.80 (d, J=16.0 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 7.16(dd, J=8.8 Hz, 2.4 Hz, 1H), 6.97 (d, J=16.0 Hz, 1H), 4.33 (d, J=7.6 Hz,1H), 4.07 (dd, J=10.0 Hz, 8.0 Hz, 1H), 3.92 (s, 3H), 3.92-3.45 (m, 17H),3.43-3.37 (m, 1H), 3.36-3.30 (m, 1H), 3.19 (dd, J=16.0 Hz, 2.4 Hz, 1H),2.96 (dd, J=16.0 Hz, 8.8 Hz, 1H), 2.82 (dd, J=12.0 Hz, 4.8 Hz, 1H), 2.00(s, 3H), 1.68 (1, J=12.0 Hz, 1H). ¹³C NMR (100 MHz, CD₃OD) δ 201.2,174.9, 174.5, 160.6, 145.5, 137.6, 131.7, 131.3, 131.2, 130.2, 128.7,126.5, 125.3, 120.5, 107.1, 105.2, 101.5, 81.7, 80.0, 77.9, 77.2, 75.8,75.0, 74.6, 74.2, 73.2, 72.5, 70.6, 70.3, 69.8, 64.64, 64.61, 62.1,55.9, 53.8, 44.2, 42.5, 22.8. HRMS (ESI): calcd for C₃₈H₅₂NO₂₀ ([M+H]⁺)842.3077, found 842.3055.

Compound 9

A mixture of 4a (50 mg, 0.13 mmol) and p-toluenesulfonyl hydrazide (32mg, 0.17 mmol) in EtOH (1.0 mL) was stirred at room temperature (25° C.)for 18 h. The mixture was purified silica gel flash columnchromatography (CH₂Cl₂/MeOH=87:13 to 80:20) to give 9 (41 mg, 57%) as alight brown solid.

Rf=0.26 (CH₂Cl₂/MeOH (5:1). ¹H NMR (400 MHz, CD₃OD) δ 7.82 (d, J=8.0 Hz,2H×⅖), 7.80 (d, J=8.0 Hz, 2H×⅗), 7.39-7.34 (m, 2H), 4.35 (d, J=7.6 Hz,1H), 3.85-3.37 (m, 11H), 3.34-3.26 (m, 1H×⅖), 3.21-3.16 (m, 1H×⅗), 3.09(t, J=8.8 Hz, 1H×⅗), 3.07 (t, J=8.8 Hz, 1H×⅖), 2.73 (dd, J=14.8 Hz, 2.8Hz, 1H×⅗), 2.65-2.55 (m, 2H×2/5), 2.42 (s, 3H), 2.27 (dd, J=14.8 Hz, 9.2Hz, 1H×⅗), 1.94 (s, 3H×⅖), 1.86 (s, 3H×⅗). ¹³C NMR (100 MHz, CD₃OD) δ159.3, 159.1, 145.2, 145.1, 137.6, 137.3, 130.5, 130.4, 129.1, 129.0,105.0, 80.8, 80.4, 80.2, 80.0, 78.5, 77.9, 77.6, 77.1, 77.0, 74.84,74.79, 74.76, 74.6, 72.52, 72.48, 70.3, 62.49, 62.46, 62.0, 61.6, 41.6,34.7, 23.9, 21.5, 17.2. HRMS (ESI): calcd for C₂₂H₃₅O₁₂N₂S ([M+H]⁺)551.1905, found 551.1871.

Compound 10

A mixture of 7aa (100 mg, 0.148 mmol) and (aminooxy)acetic acidhemihydrochloride (H₂N—O—CH₂COOH⋅½ HCl) (24.0 mg, 0.220 mmol) in DMSO(1.0 mL) was stirred at room temperature (25° C.) for 18 h. The mixturewas purified by silica gel flash column chromatography(CH₂Cl₂/MeOH=54:46 to 26:74) to give the corresponding oxime etherderivative (110 mg, 99%). A mixture of the oxime ether (100 mg, 0.134mmol), dansylcadaverine (49.0 mg, 0.146 mmol), and4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (56.0mg, 0.200 mmol) in MeOH (1.0 mL) was stirred at room temperature (25°C.) for 18 h. The mixture was purified by silica gel flash columnchromatography (CH₂Cl₂/MeOH=82:18 to 50:50) to give 10 (81.8 mg, 57%) asa pale yellow solid.

Rf=0.38 (CH₂Cl₂/MeOH (3:1). ¹H NMR (400 MHz, CD₃OD): δ 8.55 (d, J=8.8Hz, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.19 (dd, J=7.2 Hz, 0.8 Hz, 1H),7.62-7.55 (m, 2H), 7.27 (d, J=7.6 Hz, 1H), 4.44 (d, J=8.0 Hz, 1H×⅓),4.43 (d, J=8.0 Hz, 1H×⅔), 4.39 (s, 2H×⅔), 4.38 (s, 2H×⅓), 4.08-4.03 (m,1H), 3.95-3.92 (m, 1H), 3.90-3.46 (m, 16H+1H×⅓), 3.46-3.39 (m, 1H×⅔),3.34-3.30 (m, 1H), 3.18-3.11 (m, 1H), 3.09-3.00 (m, 2H), 2.95 (dd,J=14.4 Hz, 3.2 Hz, 1H×⅓), 2.88 (s, 6H), 2.88-2.80 (m, 3H), 2.71 (dd,J=14.4 Hz, 2.8 Hz, 1H×⅔), 2.58 (dd, J=14.4 Hz, 8.8 Hz, 1H×⅓), 2.28 (dd,J=14.4 Hz, 9.2 Hz, 1H×⅔), 2.01 (s, 3H), 1.96 (s, 3H×⅔), 1.90 (s, 3H×⅓),1.78-1.70 (m, 1H), 1.38-1.25 (m, 4H), 1.20-1.10 (m, 2H). ¹³C NMR (100MHz, CD₃OD) 6 175.5, 174.9, 172.5, 172.4, 160.3, 160.2, 153.2, 137.2,131.2, 131.1, 131.0, 130.1, 129.1, 124.3, 120.6, 116.4, 105.1, 101.1,81.4, 80.22, 80.17, 78.5, 78.2, 77.9, 77.6, 77.0, 75.5, 75.1, 74.9,73.1, 73.0, 72.9, 70.8, 70.1, 69.3, 69.0, 64.6, 62.7, 62.3, 54.0, 45.8,43.7, 42.1, 39.8, 39.7, 30.1, 29.8, 24.7, 22.6, 20.7, 15.1. HRMS (ESI):calcd for C₄₅H₇₀N₅O₂₂S ([M+H]⁺) 1064.4228, found 1064.4231.

INDUSTRIAL APPLICABILITY

The present invention can provide novel oligosaccharide C-glycosidederivatives which are biologically important under high stereoselective,mild, atom-economical condition.

This application claims the benefit of U.S. Provisional PatentApplication No. 62/647,241, filed Mar. 23, 2018, the disclosure of whichis incorporated by reference herein in its entirety.

1-9. (canceled)
 10. A process for preparing a compound of formula I

wherein the compound of formula I is a single diastereomer of, or withhigh diastereoselectivity with, the following β-anomer:

or a pharmaceutically acceptable salt thereof, the process comprising:reacting a compound of formula II

with a compound of formula III

wherein X is C₁₋₇alkyl, C₃₋₇cycloalkyl, halo-C₁₋₇alkyl, C₁₋₇alkoxy,halo-C₁₋₇alkoxy, C₁₋₇alkoxy-C₁₋₇alkyl, (C₁₋₇alkoxycarbonyl)-C₁₋₇alkyl,C₂₋₇alkynyl-C₁₋₇alkyl, or aryl, which are optionally substituted, R¹ isH, or a sugar residue, R² is H, or a sugar residue, and R³ is H, or asugar residue, in the presence of at least one primary or secondaryamine and at least one additive selected from the group consisting of:(a) pyrrolidine and H₃BO₃, (b) pyrrolidine and B(OMe)₃, and (c)benzylamine and H₃BO₃, to prepare the compound of formula I.
 11. Theprocess according to claim 10, wherein the compound of formula I isselected from the group consisting of:


12. The process according to claim 10, wherein an amount of the β-anomerto an amount of an α-anomer (β-anomer:α-anomer) of the compound offormula I is >10:1.
 13. The process according to claim 10, wherein anamount of the β-anomer to an amount of an α-anomer (β-anomer:α-anomer)of the compound of formula I is >20:1.
 14. A process for preparing apharmaceutical composition, comprising mixing the compound of formula Iprepared by the process according to claim 10, or a pharmaceuticallyacceptable salt thereof, with a pharmaceutically acceptable carrier toprepare the pharmaceutical composition.
 15. A process for preparing acompound of I-1

wherein the compound of formula I-1 is a single diastereomer of, or withhigh diastereoselectivity with, the following β-anomer:

or a pharmaceutically acceptable salt thereof, the process comprising:reacting a compound of formula II

with a compound of formula III

in the presence of at least one primary or secondary amine and at leastone additive selected from the group consisting of: (a) pyrrolidine andH₃BO₃, (b) pyrrolidine and B(OMe)₃, and (c) benzylamine and H₃BO₃, togive a compound of formula I

wherein the compound of formula I is a single diastereomer of, or withhigh diastereoselectivity with, the following β-anomer:

and reacting the compound of formula I with a reactant to prepare thecompound of I-1, wherein X is C₁₋₇alkyl, C₃₋₇cycloalkyl, halo-C₁₋₇alkyl,C₁₋₇alkoxy, halo-C₁₋₇alkoxy, C₁₋₇alkoxy-C₁₋₇alkyl,(C₁₋₇alkoxycarbonyl)-C₁₋₇alkyl, C₂₋₇alkynyl-C₁₋₇alkyl, or aryl, whichare optionally substituted, R¹ is H, or a sugar residue, R² is H, or asugar residue, R³ is H, or a sugar residue, R⁴ and R⁵ independently fromeach other are selected from the group consisting of H, C₁₋₇alkyl,phenyl, benzyl, piperidinyl, p-tosyl, and 1-phthalazinyl, wherein theC₁₋₇alkyl, phenyl, benzyl, piperidinyl, p-tosyl, and 1-phthalazinyl areoptionally substituted.
 16. A process for preparing a pharmaceuticalcomposition, comprising mixing the compound of formula I-1 prepared bythe process according to claim 15, or a pharmaceutically acceptable saltthereof, with a pharmaceutically acceptable carrier to prepare thepharmaceutical composition.
 17. A compound of any one of formulae I,I-1, I-1′, and I-2, or a salt thereof,

wherein: the compound of formula I is a single diastereomer of, or withhigh diastereoselectivity with, the following β-anomer:

the compound of formula I-1 is a single diastereomer of, or with highdiastereoselectivity with, the following β-anomer:

the compound of formula I-1′ is a single diastereomer of, or with highdiastereoselectivity with, the following β-anomer:

and the compound of formula I-2 is a single diastereomer of, or withhigh diastereoselectivity with, the following β-anomer:

wherein X is C₁₋₇alkyl, C₃₋₇cycloalkyl, halo-C₁₋₇alkyl, C₁₋₇alkoxy,halo-C₁₋₇alkoxy, C₁₋₇alkoxy-C₁₋₇alkyl, (C₁₋₇alkoxycarbonyl)-C₁₋₇alkyl,C₂₋₇alkynyl-C₁₋₇alkyl, or aryl, which are optionally substituted, R¹ isH, or a sugar residue, R² is H, or a sugar residue, R³ is H, or a sugarresidue, and R⁴ and R⁵ independently from each other are selected fromthe group consisting of H, and C₁₋₇alkyl, phenyl, benzyl, piperidinyl,p-tosyl, and 1 phthalazinyl, which are optionally substituted, and Y isoptionally substituted aryl.
 18. The compound according to claim 17 or asalt thereof, wherein the compound is of formula I-1, I-1′, or I-2. 19.The compound according to claim 17 or a salt thereof, wherein thecompound is selected from the group consisting of:


20. A pharmaceutical composition, comprising the compound according toclaim 17 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.
 21. A pharmaceutical composition,comprising the compound according to claim 18 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 22.A pharmaceutical composition, comprising the compound according to claim19 or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 23. The compound according to claim 17, wherein anamount of the β-anomer to an amount of an α-anomer (β-anomer:α-anomer)of the compound of formula I, I-1, I-1′, or I-2 is >10:1.
 24. Thecompound according to claim 17, wherein an amount of the β-anomer to anamount of an α-anomer (β-anomer:α-anomer) of the compound of formula I,I-1, I-1′, or I-2 is >20:1.